CN114410773A - Marker combination for predicting or diagnosing depression recurrence and application thereof - Google Patents

Marker combination for predicting or diagnosing depression recurrence and application thereof Download PDF

Info

Publication number
CN114410773A
CN114410773A CN202210102895.4A CN202210102895A CN114410773A CN 114410773 A CN114410773 A CN 114410773A CN 202210102895 A CN202210102895 A CN 202210102895A CN 114410773 A CN114410773 A CN 114410773A
Authority
CN
China
Prior art keywords
depression
recurrence
risk
protein
hif
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202210102895.4A
Other languages
Chinese (zh)
Other versions
CN114410773B (en
Inventor
王闯
徐佳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ningbo University
Original Assignee
Ningbo University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ningbo University filed Critical Ningbo University
Priority to CN202210102895.4A priority Critical patent/CN114410773B/en
Priority claimed from CN202210102895.4A external-priority patent/CN114410773B/en
Publication of CN114410773A publication Critical patent/CN114410773A/en
Priority to PCT/CN2023/072988 priority patent/WO2023143328A1/en
Application granted granted Critical
Publication of CN114410773B publication Critical patent/CN114410773B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/30—Psychoses; Psychiatry
    • G01N2800/304—Mood disorders, e.g. bipolar, depression
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/54—Determining the risk of relapse

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Analytical Chemistry (AREA)
  • Immunology (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Microbiology (AREA)
  • Pathology (AREA)
  • Genetics & Genomics (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Hematology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cell Biology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biophysics (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

The invention provides a marker combination for predicting or diagnosing the recurrence of depression and application thereof, in particular to application of reagent materials and/or instrument equipment for detecting HSP90, HIF-1 alpha, BICC1 gene and protein level in a sample from a test object in preparing test equipment for diagnosing the recurrence risk of depression. The transcripts of HSP90, HIF-1 alpha, BICC1 protein, HSP90 and BICC1 are used as peripheral blood biomarkers to detect the content of the peripheral blood biomarkers for predicting and diagnosing the recurrence of the depression, so that the accuracy of differential diagnosis of the first and recurrence of the depression can be obviously improved, the detection method is more convenient and rapid, the compliance of patients is high, and the problems of early warning of the depression and difficult recurrence diagnosis are solved. The depression recurrence risk marker can be used as a marker for diagnosing the recurrence of depression and evaluating the treatment effect of the recurrence of depression, and has the advantages of high sensitivity, specificity and the like.

Description

Marker combination for predicting or diagnosing depression recurrence and application thereof
Technical Field
The present invention belongs to the field of biological and medical technology, in particular to biomarker combinations for predicting and/or diagnosing patients with recurrent depression and related applications thereof.
Background
Depression (MDD) is an affective disorder caused by a variety of factors with a Major symptom of persistent depression, which is one of Major psychiatric disorders and is also considered as one of the most Major disabling causes. The world health organization statistics in 2019 shows that more than 3.5 hundred million people suffer from depression worldwide, and epidemiological investigation of 3 million people completed by the organization in China shows that the prevalence rate of depression in China is 3.6% in 12 months, the lifetime prevalence rate reaches 6.9%, and the prevention and treatment of depression is not slow.
Currently, the main difficulties faced in the diagnosis and treatment of depression are: firstly, antidepressant drugs have slow effect; ② the compliance of the medicine is low; thirdly, the development of new medicines is slow; high recurrence rate. Especially, easy recurrence has become the key and difficult point of increasingly aggravated depression symptoms and prevention and cure of depression. Studies have shown that 34-83% of major depressive patients develop new depressive episodes within 6 months. Notably, 60% of depressed patients are at risk of developing a new depressive episode after the first episode, while those who have had two or more episodes of depression have a recurrence rate as high as 70% to 90%. The long-term chronic depression relapse, so that the depression becomes a chronic major mental disease, and the difficulty is brought to the prevention and treatment of the depression.
Clinically, the diagnosis of the recurrence of Depression is mainly based on the detailed medical history and mental symptoms of the patient, and the comprehensive judgment is made by subjective scores such as Hamilton Depression Scale (HAMD) and montgomery Depression Scale (MADRS), and the diagnosis results are different due to different subjective experiences of doctors. In order to make the diagnosis of the recurrence of depression more objective, reduce human factors and improve the consistency and accuracy of diagnosis, researchers all over the world have been dedicated to searching biomarkers of the recurrence of depression and establishing an effective detection method in recent years. Peripheral blood of depression patients is easy to obtain, the wound is small, the price is low, automatic detection is easy, uncertain human factors in current diagnosis can be effectively assisted, misdiagnosis rate is reduced, and the marker has good sensitivity and specificity.
However, no biomarker related report of depression recurrence is currently found in the art. Therefore, there is an urgent need in the art to develop a high-sensitivity and specific marker for depression recurrence for clinical diagnosis and treatment to solve the problem of difficulty in diagnosis of depression recurrence, and a detection system for predicting and/or diagnosing the risk of depression recurrence is needed to improve the objectivity and accuracy of depression recurrence evaluation.
Disclosure of Invention
The invention aims to provide a specific marker for predicting and/or diagnosing the recurrence risk of depression with high sensitivity and high specificity and application thereof.
In a first aspect of the invention, the use of a gene, transcript, protein or detection reagent thereof of a depression recurrence risk marker for preparing a diagnostic reagent or kit for assessing the recurrence risk of depression is provided;
wherein the depression recurrence risk marker is selected from the group consisting of:
(M) a gene, transcript, or protein of one or more markers selected from M1-M3: (M1) HSP 90; (M2) HIF-1 α; (M3) BICC 1.
In another preferred embodiment, the risk marker of recurrence of depression comprises a gene, transcript, or protein of M1 marker (HSP 90).
In another preferred embodiment, the risk marker of recurrence of depression includes a gene, transcript, or protein of the M2 marker (HIF-1 α), preferably, a protein of the M2 marker (HIF-1 α).
In another preferred example, the risk marker of recurrence of depression further comprises a gene, transcript, or protein of M3 marker (BICC 1).
In another preferred embodiment, the diagnostic reagent or kit is used for detecting the level of the risk marker in a sample to be tested.
In another preferred embodiment, the sample to be tested is selected from the group consisting of: blood, plasma, serum, or a combination thereof.
In another preferred embodiment, the expression level of the risk marker comprises an expression level in blood, plasma or serum.
In another preferred embodiment, the assessment comprises an early diagnosis, an auxiliary diagnosis, or a combination thereof.
In another preferred embodiment, the gene, mRNA, cDNA, or protein of the risk marker is of human origin.
In another preferred embodiment, the detection reagent is coupled to or carries a detectable label.
In another preferred embodiment, the detectable label is selected from the group consisting of: a chromophore, a chemiluminescent group, a fluorophore, an isotope, or an enzyme.
In another preferred embodiment, the antibody is a monoclonal antibody or a polyclonal antibody.
In another preferred embodiment, the diagnostic reagent comprises an antibody, a primer, a probe, a sequencing library, a nucleic acid chip (e.g., a DNA chip), or a protein chip.
In another preferred embodiment, the nucleic acid chip comprises a substrate and specific oligonucleotide probes spotted on the substrate, wherein the specific oligonucleotide probes comprise probes specifically binding to the polynucleotide (mRNA or cDNA) of the risk marker.
In another preferred embodiment, the sample to be tested is from a subject selected from the group consisting of: a subject without depression, a subject susceptible to depression, a first-onset patient of depression, a patient with recurrent depression, or a combination thereof.
In another preferred embodiment, the kit further comprises a label or instructions for use of the kit for (a) diagnosing the risk of recurrence of depression, and/or (b) evaluating the efficacy of a treatment for recurrence of depression.
In another preferred embodiment, the label or instructions may indicate the following: if the transcript levels of HSP90 and BICC1 in the risk marker of the test subject are significantly higher than the control reference value, it is suggested that the risk of relapse of depression is higher in the test subject than in general depression patients.
In another preferred example, if the transcript levels of HSP90 and BICC1 in the risk marker of the test subject are not higher than the control reference value, it is suggested that the test subject is at a lower risk of relapse of depression.
In another preferred embodiment, the label or instructions may indicate the following: if the subject's translation level of the risk marker is significantly higher than the control reference value, it is suggested that the subject's risk of recurrence of depression is higher than that of general depression patients.
In another preferred example, if the subject's translation level of the risk marker is not higher than the control reference value, it is suggested that the subject is at a lower risk of relapse of depression.
In another preferred embodiment, the label or instructions may indicate the following:
if the risk marker concentration C1 in the test subject is significantly higher than the control reference value C0, the subject has a greater chance of recurrent depression than a general depression patient.
In another preferred embodiment, the control reference value C0 is the concentration of the risk marker in the same sample in a normal population or a patient who has not had a relapse of depression.
In another preferred embodiment, the expression "significantly higher" means that the ratio of C1/C0 is 1.5 or more, preferably 2 or more, and more preferably 3 or more.
In another preferred embodiment, if the protein amount or activity or mRNA level of HSP90 is increased, it is suggested that the test subject has an increased risk of relapse of depression.
In another preferred embodiment, an increased HIF-1 α protein level or activity is indicative of an increased risk of relapse in the subject with depression.
In another preferred embodiment, if the amount or activity of the proteins or mRNA levels of BICC1 and HSP90 is increased, it is suggested that the test subject has an increased risk of relapse of depression.
In another preferred embodiment, an increase in the amount or activity of BICC1 protein or mRNA level and HIF-1 α protein level or activity indicates an increased risk of relapse in a subject suffering from depression.
In another preferred embodiment, an increase in the amount or activity of HSP90 protein or mRNA level and the amount or activity of HIF-1 α protein is indicative of an increased risk of relapse in a subject being tested for depression.
In another preferred embodiment, an increase in the risk of recurrence of depression in a subject (an increased risk of recurrence of depression associated with decreased degradation of HIF-1. alpha. protein) is indicated if the amount or activity of HSP90 protein or mRNA level is increased and the amount or activity of HIF-1. alpha. protein is increased but HIF-1. alpha. mRNA level is not significantly changed (or unchanged).
In another preferred example, an increase in the amount or activity of protein of HSP90, HIF-1 α and BICC1 or mRNA levels of HSP90 and BICC1 is indicative of an increased risk of relapse in a subject being tested for depression.
In another preferred example, when the expression level of two or three risk marker genes or a combination thereof selected from the group consisting of C1 is significantly higher than the control reference value C0, it is suggested that the subject is at high risk of relapse of depression: (M1) HSP 90; (M2) HIF-1 α; (M3) BICC 1.
In a second aspect of the invention, there is provided a set of markers for predicting the risk of relapse of depression, said set comprising 2-3 markers selected from M1 to M3:
(M1) a gene, transcript, or protein of HSP 90;
(M2) a gene, transcript, or protein of HIF-1 α;
(M3) a gene, transcript or protein of BICC 1.
In a third aspect of the present invention, there is provided a depression recurrence risk assessment apparatus comprising:
(a) the input module is used for inputting depression recurrence risk marker data in blood, plasma or serum of a certain detection object;
wherein the risk marker gene is selected from the group consisting of:
(M) a gene, transcript, or protein of one or more markers selected from M1-M3: (M1) HSP 90; (M2) HIF-1 α; (M3) BICC 1;
(b) a data processing module for processing the depression relapse risk marker data and giving a relapse risk assessment value, wherein the processing comprises: comparing the level of transcription or expression of the inputted marker C1 to a control reference value C0, wherein when C1 is significantly higher than C0, it is indicative that the subject is at high risk of recurrence of depression; when C1 is not significantly higher than C0, the subject is indicated to have a low risk of recurrence of depression; and
(c) and the output module is used for outputting the evaluation result.
In another preferred embodiment, the expression "significantly higher" means that the ratio of C1/C0 is 1.5 or more, preferably 2 or more, and more preferably 3 or more.
In another preferred embodiment, the device further comprises a detection module for detecting the transcript level, protein level, or protein activity of the risk marker.
In another preferred embodiment, the detection module is selected from the group consisting of: a PCR detector, a sequencer, or a combination thereof.
In another preferred example, the input module is further used for inputting depression quantitative score data based on the hamilton depression scale.
In another preferred example, the processing module further performs comprehensive data processing on the quantitative depression scoring data and the recurrence risk assessment value so as to give a treatment scheme of adjuvant therapy or interventional therapy.
In another preferred example, the treatment regimen is for reducing the risk of relapse of depression in the subject, or for preventing relapse of depression in the subject.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 shows the peripheral blood HSP90, HIF-1 alpha and BICC1 protein content change chart (FIG. 1A) of the first major depressive disorder patient in example 1 of the invention, and the recurrent and non-recurrent cases after drug treatment, and the correlation analysis (FIG. 1B, C) of the change chart and the recurrence of depressive disorder.
FIG. 2 shows a scheme of a model of recurrence of Chronic Unpredictable Mild Stress (CUMS) -induced depression in example 2 of the present invention. Wherein, the test evaluation of the behavior of the depression sample is carried out by adopting a syrup preference experiment (SPT), an open field experiment (OFT), a new environment feeding inhibition experiment (NSFT) and a forced swimming experiment (FST), and the criteria of the judgment and evaluation of the behavior are as follows: (1) at baseline in the experiment, the criteria for animal inclusion were: the sugar water preference range is 60-90%, and the threading frequency range in the autonomous activity is 150-200 times/5 minutes. (2) After first 5 weeks CUMS and second 5 weeks CUMS molding, depressed-like and non-depressed-like animal screening criteria: the depressive-like mice are: sugar water preference < 60% and its drop > 30%. ② the non-depressed-like/normal control animals were: the sugar water preference range is still 60% to 90% and its drop or rise is < 30%.
FIG. 3 shows the initial evaluation of sugar water preference test (SPT) in example 2 of the present invention. After baseline testing, 150 male mice were grouped as: in NC (n-30) and CUMS (n-120), mice were evaluated for depression-like behavior by primary SPT screening.
FIG. 4 shows the test of depressive behavior after first stress in example 2 of the invention. The results of SPT, OFT, NSFT and FST depression-like behavior tests were performed on 129 SPT-screened mice after 5 weeks CUMS. The initial chronic unpredictable mild stress-induced depressive-like behavior was assessed by Round 1-SPT screening and status scoring (fig. 3), inclusion of 129 mice for 5 weeks of CUMS modeling, and SPT, OFT, NSFT, and FST depressive-like behavior testing (fig. 4A-D).
FIG. 5 shows the evaluation of depressive behavior after Fluoxetine drug treatment in example 2 of the present invention. Primary CUMS-induced mice (n ═ 107) were treated with fluxetine (flx) for 3 weeks, grouped as: the depressed behavior of mice after fluxetine drug treatment was evaluated by SPT, OFT, NSFT, FST experiments in NC + Sal (n-25), DE + Sal (n-32), DE + FLX (n-50).
FIG. 6 shows the evaluation of SPT depressive behavior of mice after Fluoxetine drug washing in example 2 of the present invention. After the first cure induction combined Fluoxeine (FLX) treatment, 87 mice were obtained in total, evaluated for depression-like behavior by SPT, OFT, NSFT, FST, with NC + Sal (n ═ 22), DE + Sal (n ═ 27), DE + FLX (n ═ 36), and evaluated for depression-like behavior by SPT after fluoxeine drug washing.
FIG. 7 shows evaluation of behavior of depression recurrence after secondary stress in example 2 of the present invention. SPT, OFT, NSFT and FST tests are carried out and analyzed after the secondary stress (RE-CUMS), 17 NC in the group, 18 secondary stress depression group (RE-CUMS-DE) and 15 secondary stress non-depression group (RE-CUMS-w/o DE) are screened by combining the SPT and the state scoring standard.
FIG. 8 shows the expression and transcriptional evaluation of prefrontal cortex HSP90, HIF-1 α, and BICC1 after recurrence of depression in example 2 of the present invention. RE-CUMS induces HSP90, HIF-1 alpha and BICC1 protein expression to be increased obviously. Whereas hsp90 and bicc1 transcriptional changes were significantly elevated, while hif-1 α showed no significant increase. The results of immunohistochemical studies show that RE-CUMS significantly induces the significant increase of HSP90 and BICC1 labeled positive neurons.
Detailed Description
The present inventors, through extensive and intensive studies, unexpectedly found for the first time novel risk markers of recurrence of depression including (M1) HSP90, (M2) HIF-1 α, and/or (M3) BICC1, and developed methods and kits for predicting and/or judging the risk of recurrence of depression, accordingly. The present invention has been completed based on this finding.
Experiments show that the depression recurrence risk marker or the combination thereof can effectively early warn or diagnose the potential risk of recurrence of depression patients, and the depression recurrence risk marker group is adopted to predict and/or detect the probability of recurrence or disease state of depression patients, has higher accuracy and specificity, and provides reference standards for early warning and/or diagnosis of recurrence of depression in clinic.
The application detection system based on the depression recurrence marker or the combination thereof provides an objective technical means for evaluating the depression recurrence, can effectively avoid the problem of diagnosis deviation caused by scale analysis and subjective experience evaluation, and provides a new detection means for improving the objectivity and accuracy of depression recurrence evaluation.
Recurrence risk marker for depression
In the present invention, the terms "risk marker of recurrence of depression of the present invention", "risk marker of recurrence of the present invention" are used interchangeably and all refer to any one or more of three risk markers of recurrence of depression of the present invention (M1) HSP90, (M2) HIF-1 α, (M3) BICC 1.
In the present invention, the risk markers of the present invention include genes (DNA), transcripts (mRNA), cDNA, proteins or combinations thereof.
The protein of the marker of the present invention may or may not contain the initiating methionine. In addition, the term also includes full-length depression recurrence risk marker proteins and fragments thereof. In the present invention, the depression recurrence risk marker protein includes its complete amino acid sequence, its secretory protein, its mutant and its functionally active fragment.
HIF-1 α is Hypoxia-inducible factor-1 α (Hypoxia-inducible factor 1-alpha), gene name: HIF1AN (Homo sapiens), UniProtKB ID: q9NWT6, NCBI Gene: 55662. and functions as a major transcriptional regulator of hypoxia-adaptive response. Under hypoxic conditions, transcription of more than 40 genes is activated, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, hipda and other protein products that increase oxygen transport or promote metabolic adaptation to hypoxia. Plays an important role in the pathophysiology of embryonic vascularization, tumor angiogenesis and ischemic diseases.
HSP90 is Heat shock protein 90(Heat shock protein HSP90) and includes an alpha subunit (Gene name: HSP90AA1-Human, UniProtKB ID: P07900, NCBI Gene: 3326) and a beta subunit (Gene name: HSP90AB1-Human, UniProtKB ID: P08238, NCBI Gene: 3326). HSP90 may promote the maturation, structural maintenance and appropriately regulated chaperones of specific target proteins, for example, involved in cell cycle control and signal transduction. Undergoes a functional cycle associated with its ATPase activity, which is critical for its chaperone activity. Participate in regulating substrate recognition, ATPase cycle and chaperonin function.
BICC1 two-tailed C homologous Protein 1(Protein bicaudal C homolog 1), gene name: BICC1-Human, UniProtKB ID: Q9H694, NCBI Gene: 80114. BICC1 acts as a potential RNA binding protein, acting as a negative regulator of Wnt signaling, and may be involved in regulating gene expression during embryonic development.
Correlation of risk marker for recurrence of depression and recurrence of depression
In the present invention, the inventors have unexpectedly found that HSP90 is involved in the initial regulation of stress-induced depression recurrence. HSP90 has been shown to bind oxygen-dependently to the PAS domain of HIF-1 α, preventing ubiquitination degradation of HIF-1 α. Therefore, the invention provides that the depression recurrence is obviously related to the up-regulation of BICC1, and stress conditions induce the over-expression of HSP90, so that the regulation and control of HIF-1 alpha are started, the intracerebral level is rapidly improved, and the stress is involved in various pathological and physiological stresses and tissue growth and development of the brain, and further the depression recurrence is induced.
In addition, based on clinical queues and basic research, the invention discovers that BICC1 is remarkably increased in peripheral blood, prefrontal cortex and hippocampus of depression patients, and further confirms that BICC1 can be used as a key molecule in a novel depression pathogenesis.
In the invention, clinical detection evidence is provided for research and prediction, and through peripheral blood analysis of peripheral blood of a first major depressive disorder patient and peripheral blood of relapsed and non-relapsed cases after drug treatment, expression levels of HSP90, HIF-1 alpha and BICC1 in major depressive disorder are found to be remarkably increased compared with a control group, and expression levels of HIF-1 alpha and BICC1 in relapsed and non-relapsed groups after drug treatment are remarkably increased compared with HSP90, HIF-1 alpha and BICC1 in the control group, so that peripheral blood HSP90, HIF-1 alpha and BICC1 of patients with relapsed depressive disorder are shown to be highly expressed. HSP90, HIF-1 alpha and BICC1 were found to have a correlation with the recurrence of depression by correlation analysis. Using these data, the present inventors developed and validated a test method/system for prediction of the risk of recurrence of depression, for predicting the risk of recurrence of depression.
CUMS (central nervous system syndrome) induced depression recurrence model
The invention also provides a model for constructing Chronic Unpredictable Mild Stress (CUMS) induced depression recurrence and a screening scheme thereof.
A preferred modeling and screening protocol may include the steps of:
step 1: basline cohort (Round 0), after baseline testing of 150 male mice, cohorts were: NC group (n ═ 30), CUMS group (n ═ 120);
step 2: SPT screening (Round 1), 150 animals were enrolled, which were grouped as: the animals of the NC group (n-30) and the CUMS group (n-120) were included in 129 animals after SPT screening, and were used for primary stress modeling and behavioral screening;
and step 3: the first post-stress depression behavior test (Round 2), enrolled in 129 animals, grouped as: the NC group (n is 25) and the CUMS group (n is 104) are screened by SPT, OFT, NSFT and FST and then are included in 107 animals for Fluoxetine drug treatment;
and 4, step 4: evaluation of depressive behaviour after Fluoxetine drug treatment (Round 3), 107 animals were selected, grouped as: NC + Sal group (n-25), DE + Sal group (n-32), DE + FLX group (n-50); after the treatment of Fluoxetine, mice (n is 107) with depression-like behaviors after treatment are obtained by screening SPT, OFT, NSFT and FST, and then are subjected to drug cleaning animal SPT screening, and 87 animals are included for secondary stress (Re-expanded CUMS);
and 5: evaluation of behavior of depression relapse after secondary stress (Round 4), 87 animals were enrolled, grouped as: NC + Sal group (n-22), DE + Sal group (n-27), DE + FLX group (n-38); after secondary stress, the stress is screened by SPT, OFT, NSFT and FST, and the stress is brought into 50 animals for evaluation of a subsequent depression recurrence mouse animal model;
step 6: mouse intracerebral HSP90, HIF-1 α, BICC1, or a combination thereof assessment (Round 5) after recurrence of depression, 50 animals were selected, grouped as: NC group (n ═ 17), RE-cum-DE group (n ═ 18), RE-cum-w/oDE group (n ═ 15), for evaluation of expression and transcriptional changes in prefrontal cortex HSP90, HIF-1 α and BICC1 after recurrence of depression.
Detection method
Based on the high expression of HSP90, HIF-1 alpha, BICC1 or the combination thereof in blood, plasma or serum, the invention also provides a corresponding method for diagnosing the recurrence of the depression.
The present invention relates to diagnostic assays for quantitative and positional detection of the gene, transcript level or protein level of HSP90, HIF-1 alpha, BICC1, or a combination thereof, markers of risk of recurrence of depression in humans. These assays are well known in the art. The genes, transcript levels and protein levels of the human depression recurrence risk markers HSP90, HIF-1 α, BICC1, or combinations thereof, detected in the assay, may be used to diagnose (including aiding in the diagnosis) the risk of recurrence of depression.
A preferred method is to perform PCR for quantitative detection of mRNA or cDNA.
A preferred method is to sequence mRNA or cDNA for quantitative detection.
One preferred method is to quantitatively detect proteins of markers of risk of recurrence of depression.
Preferably, one method of detecting the presence or absence of a marker protein in a sample is by detection using specific antibodies, which comprises: contacting the sample with a protein-specific antibody for a risk marker of recurrence of depression, HSP90, HIF-1 α, BICC1, or a combination thereof; observing whether an antibody complex is formed, wherein the formation of the antibody complex indicates that the protein of HSP90, HIF-1 alpha, BICC1 or the combination thereof which are the risk markers of the recurrence of the depression exists in the sample.
The depression recurrence risk marker protein or its polynucleotide can be used for diagnosing the recurrence of depression. A part or all of the polynucleotides of the present invention can be immobilized as probes on a microarray or a DNA chip for analyzing differential expression analysis of genes in a single nuclear cell and gene diagnosis. The anti-depression recurrence risk marker antibody can be fixed on a protein chip and used for detecting depression recurrence risk marker protein in a sample.
Based on the study of the present invention, there was a significant increase in the expression level (mRNA level or protein level) of HSP90, BICC1 gene, and the protein level of HIF-1 α in patients with recurrent depression. Thus, HSP90, HIF-1 α, BICC1 alone or in combination may be used as a marker for detecting or diagnosing (especially in the adjuvant and/or early diagnosis) the risk of relapse of depression. When detecting, if the ratio (C1/C0) of the expression level C1 of the marker gene (i.e. HSP90, HIF-1 alpha, BICC1) to the corresponding expression level C0 in normal population is more than or equal to 1.5, preferably more than or equal to 2, more preferably more than or equal to 3, then the risk of recurrence of depression can be considered to be increased. Particularly, when the expression levels of 2 or 3 markers are comprehensively detected, a more accurate detection result can be obtained.
Detection kit
Based on the correlation of the risk marker of recurrence of depression with the risk of recurrence of depression, the risk markers of recurrence of depression, HSP90, HIF-1 α, BICC1, or a combination thereof, can be diagnostic markers of the risk of recurrence of depression.
The invention also provides a kit for diagnosing the recurrence risk of depression, which contains a detection reagent used for detecting the recurrence risk markers of depression, namely HSP90, HIF-1 alpha, BICC1 gene, transcript, protein or the combination thereof. Preferably, the kit contains an antibody or immunoconjugate of the present invention, HSP90, HIF-1 α, BICC1, or an active fragment thereof, as an anti-risk of recurrence of depression marker; or a primer pair, a probe or a chip containing mRNA or cDNA of the specific amplification depression recurrence risk markers HSP90, HIF-1 alpha and BICC 1.
In another preferred embodiment, the kit further comprises a label or instructions for use in diagnosing the risk of a relapse of depression and/or evaluating the efficacy of a treatment for a relapse of depression.
The main advantages of the invention include:
(a) the risk marker can efficiently and accurately predict the recurrence risk of the depression;
(b) the detection system provided by the invention can accurately early warn and evaluate the recurrence risk of depression.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally followed by conventional conditions, such as Sambrook et al, molecular cloning: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press,1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
General procedure
Real-time fluorescent quantitative PCR
Real-time fluorescence quantitative PCR is an experimental method for applying a fluorescence energy technology to polymerase chain reaction. A fluorescent dye called SYBR Green I was used in this experiment. In a PCR reaction system, SYBR Green I can emit a fluorescent signal after being specifically doped into a DNA double strand; while SYBR dye molecules that are not incorporated into the strand do not emit any fluorescent signal. Because this method allows the increase of the fluorescent signal to be synchronized with the increase of the PCR product, that is, the intensity of the fluorescent signal emitted from the fluorescent dye is proportional to the DNA yield. Therefore, the initial concentration of the target sequence can be obtained by detecting the fluorescence signal intensity in the PCR process, thereby achieving the purpose of quantification.
Example 1
The subjects were collected into 20 patients with first-onset depression and patients with recurrent depression at Ningbo City's health hospital, Ningbo city's mental health center, affiliated to Ningbo university, and 20 age-and sex-matched healthy volunteers were recruited as controls. All doctors participating in the diagnosis work have the qualification of psychiatric medical practitioners and have the psychiatric working experience of more than 10 years, are skilled in using SCID-1 checklists, are skilled in mastering ICD-10 and DSM-V diagnosis standards, adopt Hamilton depression scale (HAMD-17) to evaluate the psychopathological state of patients, have unified operation specifications, meet the requirement of consistency detection (Kappa is 0.68-0.82), and exclude the depressed patients with complications. The study was approved by the ethical committee of ningbo university, and all subjects signed an informed consent, and 20ml venous blood was drawn on an empty stomach the next morning after enrollment for scientific research.
Diagnosis, inclusion and exclusion criteria for patients with recurrent depression, patients with first-onset depression and healthy controls:
first-onset depression patients group: (1) grouping standard: all cases meet the diagnosis standard of depressive episode (F32) in ICD-10, the episode is the first episode; (2) counting: chinese, age 18-60, primary school and above cultural degree, sex, course of disease, medication condition, etc.; (3) hamilton Depression Scale (17 items, HAMD-17) score greater than or equal to 17 points; (4) the patient himself or his legal guardian signs an informed consent; (5) are all uniformly incorporated in the Ningbo university subsidiary Ningbo City well-ning hospital and Ningbo city mental health center. (6) Exclusion criteria: the same as the above depression recurrence group.
Patients with recurrent depression group: (1) grouping standard: all cases met the diagnosis criteria of recurrent depressive disorder (F33) in ICD-10, international classification of mental and behavioral disorders, with at least one previous depressive episode; (2) counting: chinese, age 18-60, primary school and above cultural degree, sex, course of disease, medication condition, etc.; (3) hamilton Depression Scale (17 items, HAMD-17) score greater than or equal to 17 points; (4) the patient himself or his legal guardian signs an informed consent; (5) the medical records are uniformly brought into the Ningbo City well-being hospital and the Ningbo City mental health center, which are attached to Ningbo university, and have complete medical record data such as 'first diagnosis record' and 'discharge record'; (6) exclusion criteria: current or past mental disorders; combined severe or chronic somatic and cerebral organic diseases (degenerative diseases of the nervous system, brain trauma or cerebrovascular diseases); users with psychoactive substances; pregnant and lactating women; those with communication difficulties; non-matching authors; medical records, including multiple depressive episodes with no complete record at other general hospital outpatients or hospitalizations, were excluded.
Healthy control group: (1) grouping standard: no mental disease or definite somatic disease existed before and at present; family history of psychiatric disease; (2) counting: chinese, age 18-60, primary school and above cultural degree, sex, course of disease, medication condition, etc.; (3) hamilton Depression Scale (17 items, HAMD-17) score greater than or equal to 17 points; (4) exclusion criteria: the same as the depression recurrence group and the first group.
1. Analyzing the content of BICC1, HIF-1 alpha and HSP90 in peripheral blood of patients suffering from first-onset depression, patients suffering from recurrent depression and healthy control patients.
About 4ml of peripheral blood was collected from each subject and allowed to clot at room temperature for 1 hour, and then the sample was centrifuged at 3000 Xg for 10 minutes to obtain serum. The sera were then stored in a low temperature freezer at-80 ℃ or directly analyzed. An ELISA detection kit for the proteins BICC1, HIF-1 alpha and HSP90 is constructed and used for detecting and analyzing the content of BICC1, HIF-1 alpha and HSP90 proteins in peripheral blood of a first-onset depression patient, a recurrent depression patient and a healthy control patient (the content of additional patent application).
2. Correlation analysis of BICC1, HIF-1 alpha and HSP90 content in peripheral blood of patients with first-onset depression, patients with recurrent depression and healthy control patients and Hamilton depression scale.
TABLE 1 basic clinical information of the Subjects and HAMD-17 test results
Figure BDA0003493019660000121
On the basis of analysis of the content of BICC1, HIF-1 alpha and HSP90 in peripheral blood of a subject, a Hamilton depression scale (HDRS-17) of the subject is collected, and correlation analysis is carried out on the expression levels of BICC1, HIF-1 alpha and HSP90 in the peripheral blood of a healthy (Control, n-20) patient and a depression (MDD, n-20) patient by combining the scoring condition of HDRS-17.
TABLE 2 HAMD-17 score and correlation analysis of peripheral blood BICC1, HIF-1 alpha, HSP90 expression in healthy and depressed subjects
Figure BDA0003493019660000122
On the basis of analysis of the content of BICC1, HIF-1 alpha and HSP90 in peripheral blood of a subject, a Hamilton depression scale (HDRS-17) of the subject is collected, and correlation analysis is carried out on the expression levels of BICC1, HIF-1 alpha and HSP90 of the peripheral blood of the subject by combining HDRS-17 scoring condition and health (Control, n ═ 20), relapse after drug treatment of a first major depressive patient (No Recurrence, n ═ 8) and relapse after drug treatment of the first major depressive patient (Recurrence, n ═ 12).
TABLE 3 HAMD-17 score and correlation analysis of peripheral blood BICC1, HIF-1 alpha, HSP90 expression in healthy, post-treatment relapsed, post-treatment non-relapsed depressed subjects
Figure BDA0003493019660000131
And (4) conclusion: the changes of peripheral blood HSP90, HIF-1 alpha and BICC1 of the first major depressive disorder patient and the peripheral blood HSP 3526, HIF-1 alpha and BICC1 of relapsed and non-relapsed cases after drug treatment find that HSP90, HIF-1 alpha and BICC1 in major depressive disorder are obviously increased compared with a control group, and the relapse is obviously increased compared with HSP90, HIF-1 alpha and BICC1 after drug treatment (figure 1A). HSP90, HIF-1 alpha and BICC1 are found to have correlation with the recurrence of the depression through correlation analysis, HSP90, HIF-1 alpha and BICC1 are found to be biomarkers of the recurrence of the depression in clinical cases (figure 1B, C).
Example 2
Constructing a Chronic Unpredictable Mild Stress (CUMS) induced depression recurrence model (figure 2) and evaluation of relevant depression-like behaviors and brain pathological changes: 150C 57BL/6 male adult mice were selected for model construction (FIG. 3), and the CUMS model used 5 weeks of stress each time. One week after acclimation, SPT behavioral assessment was performed and healthy male mice with normal behavioural performance were screened (FIGS. 4A-D). Firstly, randomly dividing the mice into a control group and an experimental group, normally feeding the mice in the control group, giving CUMS stimulation to the mice in the experimental group for 5 weeks, and screening depression-like mice and the mice in the control group after the CUMS stimulation after 5 weeks of chronic stress. Then, depressed-like mice were divided into two groups: fluoxetine (20mg/kg/day) was administered to one group, and the same dose of physiological saline was administered to the other and control mice (FIG. 5). After one week of drug cleaning, mice recovered from fluoxetine treatment were again administered with CUMS for 5 weeks, and after 5 weeks of slow stress was completed again, mice with CUMS depression again and mice without CUMS depression again and mice in a control group were selected and studied for three groups of mice.
The CUMS method selected in the experiment comprises the following steps: cold water swimming (4 ℃, 5min), hot water swimming (42 ℃, 5min), tilting the cages (45 ℃, 24h), pair feeding (24h), fasting (24h), water deprivation (24h), day and night reversing (24h), continuous lighting (36h), wetting the cages (24h, adding proper water into the cages), wherein nine stimulations are randomly arranged to be completed within 4 weeks, and the same stimulations can not continuously appear, so that the animals can not predict the occurrence of the stimulations. The experimental group was raised in a single cage, and the control group was raised normally.
The administration method comprises the following steps: before each administration, fluoxetine hydrochloride capsules were dissolved in physiological saline to prepare a 10mg/ml fluoxetine solution, and during the administration period, rats were gavaged with fluoxetine (10mg/kg) or the same dose of physiological saline daily for 3 weeks.
A drug cleaning period: it is known that the metabolic clearance half-life of fluoxetine in human is 4-6 days, while in rat, the clearance half-life of fluoxetine is 9 hours. However, other references report that the half-life of fluoxetine in rats varies, and the drug clearance period for this experiment is one week.
Animal behavioral assessment: before the start of the experiment, after the first 4 weeks CUMS, after the first CUMS-induced recovery of the depressive-like rats and after the second 4 weeks CUMS exposure, the corresponding behavioural assessments were performed, respectively.
(1) Sugar water Preference Test (SPT): before the experiment, rats were subjected to 1 week of sugar water adaptation training, two drinking bottles were placed on each cage, respectively filled with 1% sucrose water and normal tap water, and the sucrose water was freshly prepared daily. When carrying out the experimental test of syrup preference, at first forbid water 23h, then place two bottles of water (1% cane sugar water and ordinary running water) weighed in advance on the same squirrel cage, drink 1h back, withdraw two bottles of water and weigh, calculate the preference degree of animal to the syrup: the preference (%) of animals for sugar water is sugar water consumption (g)/[ sugar water consumption (g) + tap water consumption (g) ]. The experimental time schedule was between 8:00 and 10: 30.
(2) Open-field test (OFT): the rat motility was followed using a JLBehv animal behavior analysis system purchased from jeri, shanghai, comprising an open box for field activity and a correspondingly configured computer system. The open box is made of opaque material, and has an inner diameter of 75cm long, a width of 75cm and a height of 40cm, and an outer periphery provided with a sound insulation box for video and illumination. The rat is placed in the central area of the open box, and the video equipment can automatically record the data of the motion distance, the motion times, the rest time, the motion distance of the central area, the motion average speed and the like of the rat within 5 min. After each rat finishes one field experiment, the excrement in the open box is thoroughly cleared and then the next rat is tested. The experimental time was scheduled to be between 8:00 and 14: 00.
(3) Novel Suppressed Feeding Test (NSFT): a test box with the side length of 50cm and the height of 40cm is used for spreading sawdust with the height of 2cm uniformly, and sugar pills or small food blocks are placed on white paper in the center of the box bottom. Animals are fasted for 24h before the experiment, mice are placed in the box from any box corner during the experiment, the observation is carried out for 5min through a camera system, the momentum and the time only of the mice are recorded, the anxiety and depression degrees of the mice are reflected, and then the animals are placed back in the cages to record the transaction consumption within 5min so as to eliminate the influence of appetite difference on the eating time.
(4) Forced Swimming Test (Forced Swimming Test, FST): the classical forced swimming experiment was performed in 2 days. On the first day, the mice are forced to swim in deep water at 25 ℃ for 5min, and the mice are taken out, dried at room temperature and placed into cages; the next day, forced swimming was performed for 5min under the same conditions, and the immobility time chart was observed and recorded to judge the mouse depression-like behavior, wherein the longer the immobility time, the stronger the degree of depression.
After the evaluation of depression-like behavior tests and the screening of mice are carried out by a sugar water preference experiment (SPT), an open field experiment (OFT), a new environment feeding inhibition experiment (NSFT) and a forced swimming experiment (FST) (figure 6), 17 mice are finally included in a control group (NC), 18 mice in a secondary stress depression group (RE-CUMS-DE), 15 mice in a secondary stress non-depression group (RE-CUMS-w/o DE) (figure 7), and the expression and the transcriptional change of mouse prefrontal cortex 90, HSP-1 alpha and BICC1 after the depression relapse are evaluated by a Western Blot experiment, a Realtime PCR experiment and an immunohistochemical experiment.
And (4) conclusion: western Blot results show that RE-CUMS remarkably induces HSP90, and HIF-1 alpha and BICC1 protein expression is remarkably increased. The Realtime PCR results showed that RE-CUMS significantly induced elevated transcript levels of hsp90 and bicc1, while hif-1 α showed no significant increase (FIG. 8). The results of immunohistochemical studies show that RE-CUMS significantly induces the significant increase of HSP90 and BICC1 labeled positive neurons. The results show that the genes and the corresponding proteins thereof screened by the invention comprise one or more of the following: BICC1, HSP90, HIF-1 alpha, BICC1, HSP90, HIF-1 alpha, can be used as a specific biomarker for predicting or diagnosing patients with recurrent depression.
Discussion of the related Art
In the present invention, the present inventors have unexpectedly discovered for the first time novel risk markers for recurrence of depression, including (M1) HSP90, (M2) HIF-1 α, and/or (M3) BICC 1.
In the invention, the peripheral blood HSP90, HIF-1 alpha and BICC1 are selected as biomarkers to diagnose the illness state of a patient with depression recurrence, so that an objective diagnosis method for depression recurrence can be realized, and the sensitivity and the specificity for depression diagnosis are higher.
On the other hand, HSP90, HIF-1 alpha and BICC1 are determined by constructing a mouse model for chronic unpredictable mild stress-induced depression recurrence and evaluating related depression-like behaviors and brain pathological changes, can be used as key markers for early warning or diagnosing the recurrence of depression at protein and gene levels, and can judge the potential risk of the recurrence of depression or the recurrence progress state of the depression by gene screening and protein expression level detection.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. Use of a gene, transcript, protein or detection reagent thereof of a depression recurrence risk marker for the preparation of a diagnostic reagent or kit for assessing the recurrence risk of depression;
wherein the depression recurrence risk marker is selected from the group consisting of:
(M) a gene, transcript, or protein of one or more markers selected from M1-M3: (M1) HSP 90; (M2) HIF-1 α; (M3) BICC 1.
2. The use of claim 1, wherein when the expression level of two or three risk marker genes, or a combination thereof, selected from the group consisting of C1, is significantly higher than the control reference value C0, it is indicative of a high risk of relapse of depression in the test subject: (M1) HSP 90; (M2) HIF-1 α; (M3) BICC 1.
3. The use of claim 1, wherein the kit further comprises a label or instructions for use of the kit in (a) diagnosing the risk of recurrence of depression, and/or (b) assessing the efficacy of a treatment for recurrence of depression.
4. The use according to claim 1, wherein the diagnostic reagent or kit is for detecting the level of the risk marker in a test sample.
5. The use of claim 4, wherein the sample to be tested is from a subject selected from the group consisting of: a subject without depression, a subject susceptible to depression, a first-onset patient of depression, a patient with recurrent depression, or a combination thereof.
6. A set of markers for predicting the risk of relapse into depression, said set comprising 2-3 markers selected from the group consisting of M1 to M3:
(M1) a gene, transcript, or protein of HSP 90;
(M2) a gene, transcript, or protein of HIF-1 α;
(M3) a gene, transcript or protein of BICC 1.
7. A depression relapse risk assessment apparatus, characterized in that the apparatus comprises:
(a) the input module is used for inputting depression recurrence risk marker data in blood, plasma or serum of a certain detection object;
wherein the risk marker gene is selected from the group consisting of:
(M) a gene, transcript, or protein of one or more markers selected from M1-M3: (M1) HSP 90; (M2) HIF-1 α; (M3) BICC 1;
(b) a data processing module for processing the depression relapse risk marker data and giving a relapse risk assessment value, wherein the processing comprises: comparing the level of transcription or expression of the inputted marker C1 to a control reference value C0, wherein when C1 is significantly higher than C0, it is indicative that the subject is at high risk of recurrence of depression; when C1 is not significantly higher than C0, the subject is indicated to have a low risk of recurrence of depression; and
(c) and the output module is used for outputting the evaluation result.
8. The device of claim 7, wherein the input module is further configured to input quantitative depression score data based on the Hamilton Depression Scale.
9. The device of claim 7, further comprising a detection module for detecting transcript levels, protein levels, or protein activity of said risk marker.
10. The apparatus of claim 9, wherein the detection module is selected from the group consisting of: a PCR detector, a sequencer, or a combination thereof.
CN202210102895.4A 2022-01-27 2022-01-27 Marker combination for predicting or diagnosing depression recurrence and application thereof Active CN114410773B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN202210102895.4A CN114410773B (en) 2022-01-27 Marker combination for predicting or diagnosing depression recurrence and application thereof
PCT/CN2023/072988 WO2023143328A1 (en) 2022-01-27 2023-01-18 Marker combination for predicting or diagnosing depression recurrence and use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210102895.4A CN114410773B (en) 2022-01-27 Marker combination for predicting or diagnosing depression recurrence and application thereof

Publications (2)

Publication Number Publication Date
CN114410773A true CN114410773A (en) 2022-04-29
CN114410773B CN114410773B (en) 2024-05-03

Family

ID=

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116359519A (en) * 2023-05-29 2023-06-30 中国人民解放军军事科学院军事医学研究院 CLDN5 protein, CLDN5 gene and application of modification thereof in diagnosis and/or treatment of depressive disorder
WO2023143328A1 (en) * 2022-01-27 2023-08-03 宁波大学 Marker combination for predicting or diagnosing depression recurrence and use thereof

Citations (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040185474A1 (en) * 2002-12-27 2004-09-23 Kazuhito Rokutan Method of diagnosing depression
EP1586657A1 (en) * 2004-03-29 2005-10-19 Hitachi Ltd. Method of diagnosing depression
CN101400690A (en) * 2006-01-09 2009-04-01 英国技术集团国际有限公司 Modulators of hypoxia inducible factor-1 and related uses
WO2010069129A1 (en) * 2008-12-15 2010-06-24 北京命码生科科技有限公司 Non-small cell lung cancer detection marker, detection method thereof, related reagent kit and biochip
CN101921748A (en) * 2010-06-30 2010-12-22 深圳华大基因科技有限公司 DNA molecular label for high-throughput detection of human papilloma virus
EP2542696A1 (en) * 2010-03-01 2013-01-09 Caris Life Sciences Luxembourg Holdings Biomarkers for theranostics
CN103025890A (en) * 2010-04-06 2013-04-03 卡里斯生命科学卢森堡控股 Circulating biomarkers for disease
CN104328200A (en) * 2014-11-18 2015-02-04 宁波大学 Detection kit and detection method for auxiliary diagnosis of Alzheimer's disease
CN104758316A (en) * 2015-04-24 2015-07-08 宁波大学 Pharmaceutical composition for preventing and curing diabetes itches
CN104825632A (en) * 2015-04-24 2015-08-12 宁波大学 Drug for intervention treatment of diabetic peripheral neuropathy (DPN)
CN105492906A (en) * 2013-06-14 2016-04-13 首尔大学校产学协力团 Method for detecting hypoxia or diagnosing hypoxia-related diseases
JP2017000063A (en) * 2015-06-09 2017-01-05 国立大学法人群馬大学 Examination method and examination kit of depression by biomarker
CN106458993A (en) * 2014-04-14 2017-02-22 阿尔维纳斯股份有限公司 Imide-based modulators of proteolysis and associated methods of use
CN107621545A (en) * 2017-07-26 2018-01-23 东南大学 The new application that BICC1 albumen diagnoses to mental illness
KR20190090269A (en) * 2018-01-24 2019-08-01 전남대학교산학협력단 Assessment method for diagnosing and predicting late-life depression and diagnostic kits comprising thereof
CN110702917A (en) * 2019-09-05 2020-01-17 首都医科大学附属北京安定医院 Application of serum amyloid P in preparation of products related to depression diagnosis and treatment
CN110702930A (en) * 2019-09-05 2020-01-17 首都医科大学附属北京安定医院 Application of 24-hydroxycholesterol in preparation of depression diagnosis and treatment related products
CN111351945A (en) * 2020-03-18 2020-06-30 东南大学 Application of vitamin D binding protein as marker in diagnosis of mental disease depression
US20200370092A1 (en) * 2016-11-28 2020-11-26 Carsten Korth Method and biomarkers for in vitro diagnosis of mental disorders
CN112553328A (en) * 2020-12-30 2021-03-26 浙江大学 Product for detecting gene expression level and application thereof in preparation of major depressive disorder diagnosis tool
CN113332279A (en) * 2021-05-11 2021-09-03 湖北工业大学 Application of Ganetespib compound in preparation of anti-EV 71 virus drugs
CN113528643A (en) * 2021-07-21 2021-10-22 中国人民解放军军事科学院军事医学研究院 Biomarker related to depression, and diagnostic product and application thereof

Patent Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040185474A1 (en) * 2002-12-27 2004-09-23 Kazuhito Rokutan Method of diagnosing depression
EP1586657A1 (en) * 2004-03-29 2005-10-19 Hitachi Ltd. Method of diagnosing depression
CN101400690A (en) * 2006-01-09 2009-04-01 英国技术集团国际有限公司 Modulators of hypoxia inducible factor-1 and related uses
WO2010069129A1 (en) * 2008-12-15 2010-06-24 北京命码生科科技有限公司 Non-small cell lung cancer detection marker, detection method thereof, related reagent kit and biochip
EP2542696A1 (en) * 2010-03-01 2013-01-09 Caris Life Sciences Luxembourg Holdings Biomarkers for theranostics
CN103237901A (en) * 2010-03-01 2013-08-07 卡里斯生命科学卢森堡控股有限责任公司 Biomarkers for theranostics
CN103025890A (en) * 2010-04-06 2013-04-03 卡里斯生命科学卢森堡控股 Circulating biomarkers for disease
CN101921748A (en) * 2010-06-30 2010-12-22 深圳华大基因科技有限公司 DNA molecular label for high-throughput detection of human papilloma virus
CN105492906A (en) * 2013-06-14 2016-04-13 首尔大学校产学协力团 Method for detecting hypoxia or diagnosing hypoxia-related diseases
CN106458993A (en) * 2014-04-14 2017-02-22 阿尔维纳斯股份有限公司 Imide-based modulators of proteolysis and associated methods of use
CN104328200A (en) * 2014-11-18 2015-02-04 宁波大学 Detection kit and detection method for auxiliary diagnosis of Alzheimer's disease
CN104825632A (en) * 2015-04-24 2015-08-12 宁波大学 Drug for intervention treatment of diabetic peripheral neuropathy (DPN)
CN104758316A (en) * 2015-04-24 2015-07-08 宁波大学 Pharmaceutical composition for preventing and curing diabetes itches
JP2017000063A (en) * 2015-06-09 2017-01-05 国立大学法人群馬大学 Examination method and examination kit of depression by biomarker
US20200370092A1 (en) * 2016-11-28 2020-11-26 Carsten Korth Method and biomarkers for in vitro diagnosis of mental disorders
CN107621545A (en) * 2017-07-26 2018-01-23 东南大学 The new application that BICC1 albumen diagnoses to mental illness
KR20190090269A (en) * 2018-01-24 2019-08-01 전남대학교산학협력단 Assessment method for diagnosing and predicting late-life depression and diagnostic kits comprising thereof
CN110702917A (en) * 2019-09-05 2020-01-17 首都医科大学附属北京安定医院 Application of serum amyloid P in preparation of products related to depression diagnosis and treatment
CN110702930A (en) * 2019-09-05 2020-01-17 首都医科大学附属北京安定医院 Application of 24-hydroxycholesterol in preparation of depression diagnosis and treatment related products
CN111351945A (en) * 2020-03-18 2020-06-30 东南大学 Application of vitamin D binding protein as marker in diagnosis of mental disease depression
CN112553328A (en) * 2020-12-30 2021-03-26 浙江大学 Product for detecting gene expression level and application thereof in preparation of major depressive disorder diagnosis tool
CN113332279A (en) * 2021-05-11 2021-09-03 湖北工业大学 Application of Ganetespib compound in preparation of anti-EV 71 virus drugs
CN113528643A (en) * 2021-07-21 2021-10-22 中国人民解放军军事科学院军事医学研究院 Biomarker related to depression, and diagnostic product and application thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
易志凯: "不同年龄抑郁障碍的 VEGF、HIF1、BFGF表达的临床与基础研究", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》, no. 06, pages 071 - 46 *
李红金等: "慢性间歇性低氧与抑郁症行为的相关性研究", 《中国耳鼻咽喉头颈外科》, vol. 28, no. 3, pages 178 - 181 *
赵敬会等: "模拟高原缺氧条件引起小鼠焦虑与抑郁样行为的研究:模拟高原缺氧条件引起小鼠焦虑与抑郁样行为的研究", 《第三军医大学学报》, vol. 43, no. 18, pages 1806 - 1812 *
郑霄虎等: "缺氧诱导因子1Α在抑郁模型大鼠脑组织及心肌组织中的表达研究:缺氧诱导因子1Α在抑郁模型大鼠脑组织及心肌组织中的表达研究", 《中西医结合心脑血管病杂志》, vol. 11, no. 4, pages 470 - 471 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023143328A1 (en) * 2022-01-27 2023-08-03 宁波大学 Marker combination for predicting or diagnosing depression recurrence and use thereof
CN116359519A (en) * 2023-05-29 2023-06-30 中国人民解放军军事科学院军事医学研究院 CLDN5 protein, CLDN5 gene and application of modification thereof in diagnosis and/or treatment of depressive disorder
CN116359519B (en) * 2023-05-29 2023-09-15 中国人民解放军军事科学院军事医学研究院 CLDN5 protein, CLDN5 gene and application of modification thereof in diagnosis and/or treatment of depressive disorder

Also Published As

Publication number Publication date
WO2023143328A1 (en) 2023-08-03

Similar Documents

Publication Publication Date Title
US20210341494A1 (en) Personalized Medicine Approach for Treating Cognitive Loss
EP2776553B1 (en) Biomarkers for sanfilippo syndrome and uses thereof
CN101563597A (en) Compositions and methods for diagnosis and treatment of type 2 diabetes
Tanaka et al. Plasma proteomic signatures predict dementia and cognitive impairment
Mavroconstanti et al. Decreased serum levels of adiponectin in adult attention deficit hyperactivity disorder
Rainer et al. Comparison of plasma β-globin DNA and S-100 protein concentrations in acute stroke
JP2021511389A (en) How to treat spinal muscular atrophy
EP3786305A1 (en) Biomarker for depression and use thereof
EP3545103B1 (en) Method and biomarkers for in vitro diagnosis of mental disorders
CN110988351B (en) Application of vascular cell adhesion molecule in preparing related products for diagnosis and treatment of depression
KR101620274B1 (en) Composition for diagnosis of obesity and uses thereof
Strawn et al. Acid-sensing T cell death associated gene-8 receptor expression in panic disorder
Purcell et al. The abnormal regulation of gene expression in autistic brain tissue
CN114410773B (en) Marker combination for predicting or diagnosing depression recurrence and application thereof
CN114410773A (en) Marker combination for predicting or diagnosing depression recurrence and application thereof
CN114438191B (en) Application of hypoxia inducible factor 1 alpha as marker in diagnosis of depression recurrence
Shu et al. Relationship between peripheral Blood miR-181c, miR-101, and cognitive impairment in patients with diabetes mellitus complicated with acute stroke
WO2023143327A1 (en) Use of hypoxia-inducible factor 1 alpha as marker in depression recurrence diagnosis
Pasco et al. Obesity and sarcopenic obesity characterized by low-grade inflammation are associated with increased risk for major depression in women
US20230295727A1 (en) Biomarkers for the Diagnosis of Parkinson&#39;s Disease
US20230400473A1 (en) Methods and compositions for the treatment of crohn&#39;s disease
Wen et al. Using protein microarray reveals clinical correlation between self-perception of patient and the apoptosis-related proteins in rheumatoid arthritis
Vill et al. Newborn Screening for SMA-Results After Two Years of a Large Pilot Project
Piechota et al. Gene expression profiling in whole blood stimulated ex vivo with lipopolysaccharide as a tool to predict post‐stroke depressive symptoms: Proof‐of‐concept study
CN117925807A (en) Application of UHRF2 gene in diagnosis of premature ovarian failure

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant