CN114410773B - 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

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CN114410773B
CN114410773B CN202210102895.4A CN202210102895A CN114410773B CN 114410773 B CN114410773 B CN 114410773B CN 202210102895 A CN202210102895 A CN 202210102895A CN 114410773 B CN114410773 B CN 114410773B
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CN114410773A (en
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王闯
徐佳
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Ningbo University
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Abstract

The invention provides a marker combination for predicting or diagnosing depression recurrence and application thereof, in particular to application of reagent materials and/or instrument equipment for detecting HSP90, HIF-1 alpha, BICC1 genes and protein levels in a sample from a detection subject in preparation of detection equipment for diagnosing depression recurrence risk. The HSP90, HIF-1 alpha and BICC1 proteins are singly or jointly used, the transcripts of the HSP90 and the BICC1 are used as peripheral blood biomarkers to detect the content of the transcripts for predicting and diagnosing the recurrence of the depression, the differential diagnosis accuracy of the first occurrence and the recurrence of the depression can be remarkably improved, the detection method is more convenient and rapid, the patient compliance is high, and the problems of early warning and difficult recurrence diagnosis of the depression can be solved. The marker for risk of depression recurrence can be used as a marker for diagnosing depression recurrence and evaluating depression recurrence treatment effect, 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 invention belongs to the technical field of biology and medicine, and particularly relates to biomarker combinations for predicting and/or diagnosing patients suffering from recurrent depression and related applications thereof.
Background
Depression (Major depressive disorder, MDD) is an affective disorder mental disease with sustained depression of emotion as a main symptom caused by various factors, which is one of major mental diseases and is also considered as one of the most major disability reasons. World health organization statistics in 2019 show that more than 3.5 hundred million people worldwide suffer from depression, epidemiological investigation of 3 million people completed by China organization shows that the prevalence rate of the depression in China for 12 months is 3.6%, and the prevalence rate of the depression in life reaches 6.9%, so that the prevention and treatment of the depression are not sustained.
At present, the main difficulties faced in diagnosis and treatment of depression are: ① Antidepressants have slow onset of action; ② The medication compliance is low; ③ New drugs are slow to develop; ④ High recurrence rate, etc. Especially, the recurrence of the symptoms of depression is becoming an increasingly serious key point and difficulty in preventing and treating 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 new depressive episodes after the first episode, whereas those with secondary or more episodes have a recurrence rate of up to 70% -90%. Long-term chronic depression recurs, so that depression becomes a chronic serious mental disease and brings difficulty for prevention and treatment of depression.
Clinically, the diagnosis of the recurrence of depression is mainly based on the detailed medical history and mental symptoms of the patient, and comprehensive judgment is made by subjective scores such as the hamilton depression scale (Hamilton Depression Scale, HAMD) and the montgomery depression scale (MADRS), and the diagnosis results are different due to the difference of subjective experiences of doctors. In order to make diagnosis of depression recurrence more objective, reduce human factors and improve consistency and accuracy of diagnosis, scientific researchers around the world have been working on finding biomarkers of depression recurrence in recent years, and effective detection methods are established. The peripheral blood of the patient with depression is easy to obtain, the wound is smaller, the price is low, the automatic detection is easy, uncertain artificial factors in the current diagnosis can be effectively assisted, the misdiagnosis rate is reduced, and the marker has good sensitivity and specificity.
However, no biomarker-related report of depression recurrence is currently seen in the art. Therefore, there is an urgent need in the art to develop a marker for depression recurrence with high sensitivity and specificity for clinical diagnosis, for solving the problem of difficulty in diagnosis of depression recurrence, and a detection system for predicting and/or diagnosing risk of depression recurrence, to improve 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, there is provided the use of a gene, transcript, protein, or detection reagent thereof, for the manufacture of a diagnostic reagent or kit for assessing the risk of relapse of depression;
wherein the marker for risk of recurrence of depression is selected from the group consisting of:
(M) a gene, transcript, or protein of one or more markers selected from M1-M3: (M1) HSP90; (M2) HIF-1 α; (M3) BICC1.
In another preferred embodiment, the marker for risk of depression recurrence comprises a gene, transcript, or protein of the M1 marker (HSP 90).
In another preferred embodiment, the marker for risk of depression recurrence comprises a gene, transcript, or protein of the M2 marker (HIF-1. Alpha.), preferably a protein comprising the M2 marker (HIF-1. Alpha.).
In another preferred embodiment, the marker for risk of depression recurrence further comprises a gene, transcript, or protein of the M3 marker (BICC 1).
In another preferred embodiment, the diagnostic reagent or kit is used to detect the level of the risk marker in the test sample.
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 evaluation includes early diagnosis, 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: chromophores, chemiluminescent groups, fluorophores, isotopes or enzymes.
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 polynucleotides (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 depression-susceptible subject, 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 stating that the kit is used for (a) diagnosing a risk of recurrence of depression, and/or (b) evaluating the effect of a recurrent treatment of depression.
In another preferred embodiment, the label or description refers to the following: if the transcript levels of HSP90 and BICC1 in said risk markers of the test subject are significantly higher than the control reference value, then the risk of recurrence of depression in the test subject is indicated to be higher than in normal depression patients.
In another preferred embodiment, if the transcript levels of HSP90 and BICC1 in said risk markers of the test subject are not higher than the control reference value, a lower risk of recurrence of depression is indicated in the test subject.
In another preferred embodiment, the label or description refers to the following: if the subject's translation level of the risk marker is significantly higher than the control reference value, it is suggestive that the subject's risk of relapse of depression is higher than in a normal depression patient.
In another preferred embodiment, if the subject's level of translation of the risk marker is not higher than a control reference value, a lower risk of relapse is indicated in the subject's depression.
In another preferred embodiment, the label or description refers to the following:
if the risk marker concentration C1 of the test subject is significantly higher than the control reference value C0, the subject has a greater chance of relapse depression than in a normal depression patient.
In another preferred embodiment, said control reference value C0 is the concentration of said risk marker in the same sample in a normal population or in a patient with no recurrence of depression.
In another preferred embodiment, the term "significantly higher" means that the ratio of C1/C0 is not less than 1.5, preferably not less than 2, more preferably not less than 3.
In another preferred embodiment, if the protein amount or activity or mRNA level of HSP90 is increased, an increase in the risk of recurrence of depression in the subject is indicated.
In another preferred embodiment, an increase in the amount or activity of HIF-1α protein is indicative of an increased risk of recurrence of the disorder in the subject with depression.
In another preferred embodiment, if the amount or activity of proteins or mRNA levels of BICC1 and HSP90 are increased, an increase in the risk of recurrence of depression is indicated in the subject.
In another preferred embodiment, an increased risk of recurrence of depression is indicated in the subject if the amount or activity of protein or mRNA level of BICC1 and the amount or activity of protein of HIF-1α are increased.
In another preferred embodiment, an increased risk of recurrence of depression is indicated in the subject if the amount or activity of HSP90 protein or mRNA levels and the amount or activity of HIF-1α protein are increased.
In another preferred embodiment, if HSP90 protein amount or activity or mRNA level is increased and HIF-1α protein amount or activity is increased but HIF-1α mRNA level is not significantly changed (or is unchanged), then an increase in risk of recurrence of depression (an increase in risk of recurrence of depression associated with decreased degradation of HIF-1α protein) is indicated in the subject.
In another preferred embodiment, an increased risk of recurrence of depression is indicated in the subject if the amount or activity of protein of HSP90, HIF-1. Alpha. And BICC1 or the mRNA levels of HSP90 and BICC1 are increased.
In another preferred embodiment, a significantly higher expression level C1 of two or three risk marker genes or a combination thereof selected from the following group than the control reference value C0 is indicative of a high risk of relapse in the subject: (M1) HSP90; (M2) HIF-1 α; (M3) BICC1.
In a second aspect of the invention there is provided a set of markers for use in predicting risk of relapse of 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 a;
(M3) genes, transcripts, or proteins of BICC 1.
In a third aspect of the present invention, there is provided a depression recurrence risk assessment device, the device comprising:
(a) The input module is used for inputting depression recurrence risk marker data in blood, blood plasma or blood 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) HSP90; (M2) HIF-1 α; (M3) BICC1;
(b) A data processing module for processing depression recurrence risk marker data and giving a recurrence risk assessment value, wherein the processing comprises: comparing the transcription or expression level C1 of the input marker with a control reference value C0, wherein when C1 is significantly higher than C0, it is indicative of a high risk of relapse of depression in the subject; when C1 is not significantly higher than C0, then suggesting that the subject has a low risk of relapse of depression; and
(C) And the output module is used for outputting the evaluation result.
In another preferred embodiment, the term "significantly higher" means that the ratio of C1/C0 is not less than 1.5, preferably not less than 2, more preferably not less than 3.
In another preferred embodiment, the device further comprises a detection module for detecting transcript levels, protein levels, 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 embodiment, the input module is further configured to input depression quantitative score data based on the hamiltonian depression scale.
In another preferred embodiment, the processing module further performs comprehensive data processing on the depression quantitative score data and the recurrence risk assessment value, so as to give a treatment scheme of adjuvant treatment or intervention treatment.
In another preferred embodiment, the treatment regimen is used to reduce the risk of relapse of depression in the test subject, or to prevent relapse of depression in the test subject.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
FIG. 1 shows a graph of protein content changes of HIF-1. Alpha. And BICC1 (FIG. 1A) and analysis of correlation with relapse of depression in peripheral blood of patients with major depressive disorder and peripheral blood HSP90 of cases with relapse and without relapse after drug treatment in example 1 of the present invention (FIGS. 1B and C).
Figure 2 shows a scheme of a Chronic Unpredictable Mild Stress (CUMS) induced depression relapse model in example 2 of the present invention. Wherein, adopt syrup preference experiment (SPT), field experiment (OFT), new environment eating inhibition experiment (NSFT) and forced swimming experiment (FST) to carry out depression-like behavior test evaluation, the standard of behavioral judgement evaluation is as follows: (1) experimental baseline period, animal inclusion criteria were: the preference range of sugar water is 60% -90%, and the threading frequency in autonomous activities is 150-200 times/5 minutes. (2) Criteria for screening animals in depressive and non-depressive samples after first 5 week CUMS and second 5 week CUMS modeling: ① The depression-like mice were: sugar water prefers <60% and its drop is >30%. ② The non-depressive/normal control animals were: the sugar water preference range is still 60% -90% and its declining or rising amount is <30%.
FIG. 3 shows a primary sugar water preference test (SPT) evaluation in example 2 of the present invention. After baseline detection, 150 male mice were grouped into: NC group (n=30), CUMS group (n=120), mice were assessed for depression-like behavior via primary SPT screening.
Figure 4 shows the depression behavior test after first stress in example 2 of the present invention. After 129 SPT screening, mice were subjected to 5 weeks of CUMS and then tested for SPT, OFT, NSFT and FST depression-like behavior, respectively. Primary chronic unpredictable mild stress-induced depressive-like behavior was assessed via Round 1-SPT screening and status scoring (fig. 3), incorporating 129 mice for 5 weeks of CUMS modeling, via SPT, OFT, NSFT and FST depressive-like behavior testing (fig. 4A-D).
Figure 5 shows the assessment of depression behavior following Fluoxetine drug treatment in example 2 of the present invention. Primary CUMS-induced mice (n=107) were given Fluoxetine (FLX) treatments for 3 weeks, which were grouped as: nc+sal (n=25), de+sal (n=32), de+flx (n=50), mice depression behavior after Fluoxetine drug treatment was evaluated by SPT, OFT, NSFT, FST experiments.
Figure 6 shows evaluation of SPT depression behavior in mice after Fluoxetine drug washout in example 2 of the present invention. After the first cure by CUMS induction in combination with Fluoxetine (FLX), 87 mice were obtained in total for inclusion, with nc+sal group (n=22), de+sal group (n=27), de+flx group (n=36), and mice after washing with Fluoxetine drug were evaluated for depression-like behavior by SPT.
Figure 7 shows the assessment of depression recurrence behaviour following secondary stress in example 2 of the present invention. Performing SPT, OFT, NSFT and FST tests and analysis after secondary stress (RE-CUMS), screening 17 NC entry groups by combining SPT and state scoring criteria, 18 secondary stress depression groups (RE-CUMS-DE), and 15 secondary stress non-depression groups (RE-CUMS-w/oDE).
FIG. 8 shows the evaluation of HSP90, HIF-1α and BICC1 expression and transcription of prefrontal cortex after recurrence of depression in example 2 of the present invention. RE-CUMS significantly induced HSP90, HIF-1α and BICC1 protein expression significantly increased. Whereas hsp90 and bicc1 transcriptional changes were significantly elevated, hif-1α did not show significant elevation. The result of immunohistochemical study shows that RE-CUMS significantly induces significant elevation of HSP90 and BICC1 marked positive neurons.
Detailed Description
The present inventors have unexpectedly found, through extensive and intensive studies, a novel risk marker for depression recurrence including (M1) HSP90, (M2) HIF-1α, and/or (M3) BICC1 for the first time, and have accordingly developed a method and a kit for predicting and/or judging the risk of depression recurrence. The present invention has been completed on the basis of this finding.
Experiments show that the risk marker for relapse of depression or the combination thereof can effectively early warn or diagnose the potential risk of relapse of depression patients, and the risk marker group for relapse of depression is adopted to predict and/or detect the possibility of relapse or disease state of depression patients, has higher accuracy and specificity, and provides reference standard for early warning and/or diagnosis of relapse of depression in clinic.
The application detection system based on the marker or the combination of the marker for the depression recurrence provides a relatively objective technical means for evaluating the depression recurrence, can effectively avoid the diagnosis deviation problem caused by scale analysis and subjective experience evaluation, and provides a new detection means for improving the objectivity and the accuracy of depression recurrence evaluation.
Marker for risk of relapse of depression
In the present invention, the terms "risk of depression recurrence marker of the present invention", "risk of recurrence marker of the present invention" and "risk marker of the present invention" are used interchangeably to refer to any one or more of (M1) HSP90, (M2) HIF-1 α, (M3) BICC1 having three risk of depression recurrence markers of the present invention.
In the present invention, the risk markers of the present invention include genes (DNA), transcripts (mRNA), cdnas, proteins, or combinations thereof.
The proteins of the markers of the invention may or may not contain an initiating methionine. In addition, the term also includes full-length depression recurrence risk marker proteins and fragments thereof. In the present invention, the marker protein for risk of depression recurrence includes its complete amino acid sequence, its secretory protein, its mutant and its functionally active fragment.
HIF-1α is hypoxia inducible factor-1α (Hypoxia-inducible factor-alpha), gene name: HIF1AN (Homo sapiens), uniProtKB ID: q9NWT6, NCBI Gene:55662. acts as the primary transcriptional regulator of hypoxia adaptive response. Under hypoxic conditions, transcription of more than 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA and other protein products, increase oxygen transport or promote metabolism to accommodate hypoxia. Plays an important role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic diseases.
HSP90 is a heat shock protein 90 (Heat shock protein HSP 90) comprising an alpha subunit (Gene name: HSP90AA1-Human, uniProtKB ID: P07900, NCBI Gene: 3326) and a beta subunit (Gene name: HSP90AB1-Human, uniProtKB ID: P08218, NCBI Gene: 3326). HSP90 may promote specific target protein maturation, structural maintenance, and appropriately regulated chaperones, such as those involved in cell cycle control and signal transduction. Undergo a functional cycle associated with its atpase activity, which is critical to its chaperone activity. Is involved in regulating substrate recognition, atpase cycle and chaperonin function.
BICC1 double-tail C homologous protein 1 (Protein bicaudal C homolog), gene name: BICC1-Human, uniProtKB ID: Q9H694, NCBI Gene:80114.BICC1, a potential RNA-binding protein, acts as a negative regulator of Wnt signaling, possibly involved in regulating gene expression during embryonic development.
Correlation of risk markers for relapse of depression and relapse of depression
In the present invention, the inventors have unexpectedly found that HSP90 is involved in the initiation of regulation of stress-induced depression recurrence. Studies have shown that HSP90 can bind oxygen-dependently to the PAS region of HIF-1α, preventing ubiquitination degradation of HIF-1α. Therefore, the invention proposes that the recurrence of depression is obviously related to the upregulation of BICC1, and the stress condition induces the overexpression of HSP90, thereby starting the regulation of HIF-1 alpha, rapidly improving the level in brain, participating in the growth and development of various pathologies, physiological stress and tissues of the brain, and further inducing the recurrence of depression.
In addition, in the invention, based on clinical queues and basic researches, BICC1 is found to be remarkably increased in peripheral blood and prefrontal cortex and hippocampus of depression patients, and further it is clear that BICC1 can be used as a key molecule in the pathogenesis of novel depression.
In the invention, clinical detection evidence is provided for research prediction by the inventor, and through the analysis of peripheral blood of a patient suffering from major depression and peripheral blood of recurrent and unrepeated cases of patients after drug treatment, the expression levels of HSP90, HIF-1α and BICC1 in the major depression are obviously increased compared with the difference of a control group, and compared with the difference of HSP90, HIF-1α and BICC1 in the recurrent patients after drug treatment, the expression levels of HIF-1α and BICC1 are obviously increased compared with the difference of the control group, so that the high expression of HSP90, HIF-1α and BICC1 in the peripheral blood of the patients suffering from depression is shown. Correlation analysis shows that HSP90, HIF-1 alpha and BICC1 have correlation with depression recurrence. Using these data, the present invention developed and validated a detection method/system for predicting risk of relapse in depression.
CUMS-induced depression recurrence model
The invention also provides a method for constructing a Chronic Unpredictable Mild Stress (CUMS) induced depression recurrence model and a screening scheme thereof.
A preferred construction model and screening protocol may comprise the steps of:
Step 1: basline (Round 0), 150 male mice were baseline tested and were assigned: NC group (n=30), CUMS group (n=120);
Step 2: SPT screening (Round 1), 150 animals were enrolled and grouped into: NC group (n=30), CUMS group (n=120), 129 animals were enrolled after SPT screening for primary stress modeling and behavioral screening;
Step 3: post-first stress depressive behavioral testing (Round 2), 129 animals were enrolled and grouped into: NC group (n=25), CUMS group (n=104), animals 107 were enrolled after SPT, OFT, NSFT, FST screening for Fluoxetine drug treatment;
Step 4: fluoxetine post-drug treatment depressive behavioral assessment (Round 3), 107 animals were enrolled and grouped as: nc+sal group (n=25), de+sal group (n=32), de+flx group (n=50); mice with depression-like behavior after treatment (n=107) were obtained by SPT, OFT, NSFT, FST screening after Fluoxetine drug treatment, drug-washed, and then drug-washed animal SPT screening, incorporating 87 animals for secondary stress (Re-exposed CUMS);
Step 5: evaluation of depression recurrence behavior after secondary stress (Round 4), 87 animals were selected and grouped as: nc+sal group (n=22), de+sal group (n=27), de+flx group (n=38); after secondary stress, 50 animals are included for evaluation of a follow-up depression recurrent mouse animal model through SPT, OFT, NSFT, FST screening;
Step 6: evaluation of HSP90, HIF-1 a, BICC1, or combinations thereof (Round 5) in mice brains after recurrence of depression, 50 animals were enrolled and grouped into: NC group (n=17), RE-CUMS-DE group (n=18), RE-CUMS-w/oDE group (n=15) for evaluation of prefrontal cortex HSP90, HIF-1 a and BICC1 expression and transcriptional changes after depression recurrence.
Detection method
Based on the high expression of HSP90, HIF-1 alpha, BICC1 or a combination thereof in blood, plasma or serum, which is a risk marker for depression recurrence, the present invention also provides a corresponding method for diagnosing depression recurrence.
The present invention relates to diagnostic assays for the quantitative and localized detection of gene, transcript level or protein level of the human depression recurrence risk markers HSP90, HIF-1 alpha, BICC1, or combinations thereof. Such tests are well known in the art. The gene, transcript level and protein level of the human depression recurrence risk markers HSP90, HIF-1 alpha, BICC1, or combinations thereof, detected in the assay, may be used to diagnose (including aid in diagnosis of) the risk of depression recurrence.
A preferred method is to perform quantitative PCR on mRNA or cDNA.
One preferred method is to quantitatively detect mRNA or cDNA, sequencing.
One preferred method is to quantitatively detect the protein of a marker for risk of depression recurrence.
Preferably, one method of detecting the presence or absence of a marker protein in a sample is by using a specific antibody, which comprises: contacting the sample with a protein-specific antibody of a depression recurrence risk marker HSP90, HIF-1 a, BICC1, or a combination thereof; observing whether an antibody complex is formed, wherein the formation of an antibody complex indicates the presence of a protein of the depression recurrence risk marker HSP90, HIF-1 alpha, BICC1, or a combination thereof in the sample.
The marker protein or the polynucleotide for risk of depression recurrence can be used for diagnosis of depression recurrence. A part or all of the polynucleotides of the present invention can be immobilized as probes on a microarray or DNA chip for analysis of differential expression of genes in mononuclear cells and for gene diagnosis. The antibodies to the risk of depression relapse markers may be immobilized on a protein chip for detection of the risk of depression relapse marker proteins in the sample.
Based on the studies of the present invention, there was a significant increase in the amount of expression (mRNA level or protein level) of HSP90, BICC1 genes and protein level of HIF-1α in patients with recurrent depression. Thus, HSP90, HIF-1 a, BICC1, alone or in combination, may be used as a marker to detect or diagnose (especially to aid diagnosis and/or early diagnosis) the risk of recurrence of depression. In detection, if the ratio (C1/C0) of the expression level C1 of the marker gene (namely HSP90, HIF-1. Alpha., BICC 1) to the corresponding expression level C0 in the normal population is not less than 1.5, preferably not less than 2, more preferably not less than 3, it is considered that the risk of relapse of depression is increased. In particular, when the expression level of 2 or 3 markers is comprehensively detected, more accurate detection results can be obtained.
Detection kit
Because of the correlation of the risk of depression recurrence marker with the risk of depression recurrence, the risk of depression recurrence marker HSP90, HIF-1 a, BICC1, or a combination thereof may be used as a diagnostic marker of the risk of depression recurrence.
The invention also provides a kit for diagnosing the recurrence risk of depression, which comprises a detection reagent for detecting the recurrence risk marker HSP90, HIF-1 alpha, BICC1 gene, transcript, protein or combination thereof. Preferably, the kit contains an antibody or immunoconjugate of the anti-depression recurrence risk marker HSP90, HIF-1 a, BICC1 of the invention, or an active fragment thereof; or a primer or primer pair, probe or chip containing mRNA or cDNA specifically amplifying depression recurrence risk markers HSP90, HIF-1 alpha, BICC 1.
In another preferred embodiment, the kit further comprises a label or instructions stating that the kit is used for diagnosing a risk of depression recurrence and/or evaluating the therapeutic effect of depression recurrence.
The main advantages of the invention include:
(a) The risk marker can efficiently and accurately predict the recurrence risk of depression;
(b) The detection system can accurately early warn and evaluate the recurrence risk of depression.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedure, which does not address the specific conditions in the examples below, is generally followed by routine conditions, such as, for example, sambrook et al, molecular cloning: conditions described in the laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989) or as recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
General method
Real-time fluorescent quantitative PCR
Real-time fluorescent quantitative PCR is an experimental method that applies fluorescent energy technology to the polymerase chain reaction. A fluorescent dye called SYBR Green I was used in this experiment. In a PCR reaction system, SYBR Green I emits a fluorescent signal after being specifically doped into a DNA double strand; while SYBR dye molecules that are not incorporated into the chain do not emit any fluorescent signal. Because this method allows the increase in fluorescence signal to be synchronized with the increase in PCR product, that is, the intensity of fluorescence signal emitted by the fluorescent dye is proportional to DNA yield. Therefore, the initial concentration of the target sequence can be obtained by detecting the fluorescence signal intensity in the PCR process, so that the aim of quantification can be fulfilled.
Example 1
The subjects were 20 cases of first-onset depression patients and recurrent depression patients uniformly incorporated by Ningbo university affiliated Ningbo city corning hospital, ningbo city mental health center, and 20 healthy volunteers matched in age and sex were recruited as controls. All physicians involved in the diagnosis work were qualified as psychiatric practitioners and had more than 10 years of psychiatric practice experience, were proficiently informed with SCID-1 checkup tables, were proficiently informed with ICD-10 and DSM-V diagnostic criteria, were evaluated for their psychopathological state using the Hamiltonian depression scale (HAMD-17), were uniformly operated, were consistent with compliance detection requirements (kappa=0.68-0.82), and were excluded from depressed patients with complications. The study was approved by the ethics committee of the university of Ningbo, all study subjects signed informed consent, and 20ml venous blood was drawn on an empty stomach the next morning after the group was entered for scientific study.
Recurrent depression patients, primary depression patients, and healthy control diagnosis, inclusion and exclusion criteria:
Group of patients with first-onset depression: (1) group entry criteria: all cases meet the (F32) diagnosis standard of depressive episode in ICD-10 of International Classification of mental and behavioral disorders, the episode is the first episode; (2) statistics: han nationality, 18-60 years old, primary school and above cultural degree, sex half, course of disease, medication condition, etc.; (3) Hamilton depression scale (17 items, HAMD-17) score equal to or greater than 17 points; (4) The patient himself or his legal guardian signs an informed consent; (5) Are uniformly incorporated in the Ningbo city corning hospital and Ningbo city mental health center attached to Ningbo university. (6) exclusion criteria: the same as above depression recurrence group.
Group of patients with recurrent depression: (1) group entry criteria: all cases meet the diagnostic standard of recurrent depressive disorder (F33) in ICD-10 of International Classification of mental and behavioral disorders, and at least one depressive episode has been in the past; (2) statistics: han nationality, 18-60 years old, primary school and above cultural degree, sex half, course of disease, medication condition, etc.; (3) Hamilton depression scale (17 items, HAMD-17) score equal to or greater than 17 points; (4) The patient himself or his legal guardian signs an informed consent; (5) Are uniformly incorporated in the Ningbo university affiliated Ningbo city corning hospital and Ningbo city mental health center, and have complete medical record data such as 'first diagnosis record' and 'discharge record'; (6) exclusion criteria: other mental disorders are present or past; combining severe or chronic somatic diseases and cerebral organic diseases (neurodegenerative diseases, brain trauma or cerebrovascular diseases); a user with a psychoactive substance; pregnant and lactating women; a person with difficulty in communication; non-collaborators; including medical records where multiple episodes of depression are not fully recorded due to clinic or hospitalization in other general hospitals, are excluded.
Healthy control group: (1) group entry criteria: past and current no mental illness and clear somatic illness; no family history of mental illness; (2) statistics: han nationality, 18-60 years old, primary school and above cultural degree, sex half, course of disease, medication condition, etc.; (3) Hamilton depression scale (17 items, HAMD-17) score equal to or greater than 17 points; (4) exclusion criteria: the same as the depression recurrence group and the first onset group.
1. And (3) analyzing the contents of BICC1, HIF-1 alpha and HSP90 in peripheral blood of patients suffering from primary depression and patients suffering from recurrent depression and healthy control patients.
About 4ml of peripheral blood was collected from each subject and allowed to coagulate at room temperature for 1 hour, and then the sample was centrifuged at 3000×g for 10 minutes to obtain serum. The serum was then stored in a low temperature refrigerator at-80 ℃ or analyzed directly. The BICC1, HIF-1 alpha and HSP90 protein ELISA detection kit is constructed and is used for detecting and analyzing the content of the BICC1, HIF-1 alpha and HSP90 proteins in peripheral blood of patients with first depression, patients with recurrent depression and healthy control patients (the content of additional patent declaration).
2. And (3) carrying out correlation analysis on the content of BICC1, HIF-1 alpha and HSP90 in peripheral blood of patients suffering from primary depression and patients suffering from recurrent depression and healthy control patients and the Hamiltonian depression scale.
TABLE 1 subject basic clinical information and HAMD-17 detection results
Based on the analysis of the content of BICC1, HIF-1 alpha and HSP90 in the peripheral blood of a subject, the Hamiltonian depression scale (HDRS-17) of the patient is collected, and the correlation analysis is carried out on the expression level of the BICC1, HIF-1 alpha and HSP90 in the peripheral blood of the patient with the health (Control, n=20) and depression (MDD, n=20) by combining the scoring condition of the HDRS-17.
TABLE 2 analysis of correlation of HAMD-17 score and peripheral blood BICC1, HIF-1. Alpha., HSP90 expression in healthy and depressed subjects
Based on the analysis of the content of BICC1, HIF-1 alpha and HSP90 in the peripheral blood of a subject, collecting the Hamiltonian depression scale (HDRS-17) of the patient, and carrying out correlation analysis by combining the scoring condition of the HDRS-17 with the health (Control, n=20), the relapse prevention after the drug treatment of the patients suffering from the first major depression (No recurrence, n=8) and the relapse prevention after the drug treatment of the patients suffering from the first major depression (Recurrence, n=12) of the peripheral blood BICC1, HIF-1 alpha and HSP90 expression levels of the patients.
TABLE 3 analysis of HAMD-17 score and peripheral blood BICC1, HIF-1α, HSP90 expression correlation for healthy, post-treatment relapsed, post-treatment non-relapsing depressive subjects
Conclusion: the changes of peripheral blood HSP90, HIF-1 alpha and BICC1 of patients with major depressive disorder and recurrent and unrepeated cases after drug treatment find that HSP90, HIF-1 alpha and BICC1 in major depressive disorder are obviously increased compared with the control group, and that HSP90, HIF-1 alpha and BICC1 are obviously increased compared with the unrepeated groups after drug treatment (figure 1A). Correlation analysis shows that HSP90, HIF-1 alpha and BICC1 have correlation with depression recurrence, and clinical cases initially show that HSP90, HIF-1 alpha and BICC1 are biomarkers of depression recurrence (FIGS. 1B and C).
Example 2
Construction of a Chronic Unpredictable Mild Stress (CUMS) induced depression recurrence model (fig. 2) and associated depression-like behavior and brain pathological change assessment: 150C 57BL/6 male adult mice were selected for model construction (FIG. 3), and the CUMS model was stressed 5 weeks at a time. One week after the mice were acclimatized, SPT behavioural assessment was performed to screen healthy male mice with normal behavioural performance (FIGS. 4A-D). First, mice were randomly divided into a control group and an experimental group, mice in the control group were normally bred, mice in the experimental group were given a 5-week cure stimulation, and mice in the depression-like after cure stimulation and mice in the control group were selected after 5-week chronic stress was completed. Then, the depression-like mice were divided into two groups: one group was given Fluoxetine (20 mg/kg/day) and the other and control groups were given the same dose of physiological saline (FIG. 5). After one week of drug washout, mice recovered from fluoxetine treatment were given a second 5 week cure, and after 5 week slow stress was completed, mice were screened out as re-cure depression mice and mice as non-depression mice after re-cure and mice in the control group, and three groups of mice were studied.
The CUMS method adopted in the experiment comprises the following steps: cold water swimming (4 ℃,5 min), hot water swimming (42 ℃,5 min), tilting squirrel cages (45 ℃,24 h), paired feeding (24 h), fasted (24 h), water forbidden (24 h), day-night inversion (24 h), continuous lighting (36 h), moist squirrel cages (24 h, proper water is added into squirrel cages), nine stimulation options are randomly arranged to be completed within 4 weeks, and the same stimulation cannot occur continuously, so that animals cannot predict the occurrence of stimulation. The experimental group is fed in a single cage, and the control group is fed normally.
The administration method comprises the following steps: before each administration, fluoxetine hydrochloride capsules were dissolved in physiological saline to prepare 10mg/ml fluoxetine solution, and rats were gavaged daily for 3 weeks with fluoxetine (10 mg/kg) or the same dose of physiological saline.
Drug wash period: the metabolic clearance half-life of fluoxetine in humans is known to be 4-6 days, whereas in rats the clearance half-life of fluoxetine is 9 hours. However, other references report that the clearance half-life of fluoxetine in rats varies from one week to another, and the drug clearance period in this experiment is one week.
Animal behavioral assessment: corresponding behavioral assessments were performed after the first 4 week cure before the start of the experiment, after the first cure-induced depression-like rats recovered and after the second 4 week cure exposure, respectively.
(1) Sugar water preference experiment (sugar PREFERENCE TEST, SPT): before the experiment starts, rats are trained in syrup adaptability for 1 week, two drinking bottles are placed on each squirrel cage, 1% of sucrose water and ordinary tap water are respectively filled, and the sucrose water is freshly prepared every day. When the syrup preference experiment test is carried out, firstly, water is forbidden for 23 hours, then two bottles of water (1% of sucrose water and common tap water) weighed in advance are placed on the same squirrel cage, after drinking for 1 hour, the two bottles of water are removed and weighed, and the preference of animals to syrup is calculated: preference (%) of animals for sugar water=sugar water consumption (g)/[ sugar water consumption (g) +tap water consumption (g) ]. The experimental schedule was performed between 8:00 and 10:30.
(2) Open field experiment (Open-FIELD TEST, OFT): the activity capacity of rats was tracked using a JLBehv animal behavioral analysis system from Shanghai Jili, which included an open box for field activity and a correspondingly configured computer system. The open box is made of opaque materials, has an inner diameter of 75cm x 40cm, and has a video screen and an illuminated sound-proof box at the periphery. The rat is placed in the central area of the open box, and the video equipment can automatically record the data such as the moving distance, the moving times, the rest time, the moving distance and the moving average speed of the central area of the rat within 5 minutes. After each rat finishes one open field experiment, the excrement in the open box needs to be thoroughly removed before the next rat is tested. The experimental schedule was between 8:00 and 14:00.
(3) New Environment feeding inhibition experiment (Novelty Suppressed FEEDING TEST, NSFT): a test box with 50cm side length and 40cm height is used, wood chips with the height of 2cm are evenly paved on the box bottom, and sugar pellets or small food blocks are placed on white paper at the center of the box bottom. Animals were fasted for 24h before the experiment, mice were placed into the box from any box angle during the experiment, the moment and the time only of the mice were recorded by observing through a camera system for 5min, the anxiety and depression degree of the mice were reflected, and then the animals were placed back into the cage for recording the transaction consumption in 5min, so as to eliminate the influence of appetite difference on feeding time.
(4) Forced swimming test (Forced SWIMMING TEST, FST): classical forced swimming experiments were performed in 2 days. The first day, the mice are forced to swim in the deep water at 25 ℃ for 5min, taken out and dried at room temperature, and put into cages; the following day, forced swimming was performed under the same conditions for 5min, and a immobility time chart was observed and recorded to determine the mouse's depression-like behavior, wherein the longer the immobility time, the stronger the depression.
After evaluation of depression-like behavior test and mouse screening by sugar water preference test (SPT), field test (OFT), new environment eating inhibition test (NSFT) and Forced Swimming Test (FST) (FIG. 6), 17 mice were finally included in control group (NC), 18 mice were included in secondary stress depression group (RE-CUMS-DE), 15 mice were included in secondary stress non-depression group (RE-CUMS-w/o DE) (FIG. 7), and HSP90, HIF-1 alpha and BICC1 expression and transcriptional changes of the prefrontal leaf cortex of mice after depression recurrence were evaluated by Western Blot test, REALTIME PCR test and immunohistochemical test.
Conclusion: western Blot results show that RE-CUMS significantly induces HSP90, HIF-1 alpha and BICC1 protein expression to be significantly increased. REALTIME PCR results indicate that RE-CUMS significantly induced elevated hsp90 and bicc1 transcript levels, whereas hif-1α did not show significant elevation (FIG. 8). The result of immunohistochemical study shows that RE-CUMS significantly induces significant elevation of HSP90 and BICC1 marked positive neurons. The results show that the selected genes and the corresponding proteins thereof 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 invention
In the present invention, the inventors have unexpectedly discovered a novel risk of depression recurrence marker that includes (M1) HSP90, (M2) HIF-1 a, and/or (M3) BICC1.
In the invention, peripheral blood HSP90, HIF-1 alpha and BICC1 are selected as biomarkers to diagnose the illness state of a patient with recurrent depression, so that an objective diagnosis method for recurrent depression can be realized, and the diagnosis of depression has higher sensitivity and specificity.
On the other hand, by constructing a chronic unpredictable mild stress induced depression recurrence mouse model and evaluating related depression-like behaviors and brain pathological changes, HSP90, HIF-1 alpha and BICC1 are determined, and can be used as key markers for early warning or diagnosis of depression recurrence at protein and gene levels, and the potential risk of depression recurrence or depression recurrence progress state can be judged through gene screening and protein expression level detection.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (19)

1. The use of a marker for risk of relapse of depression, characterized by the preparation of a diagnostic reagent or kit comprising an antibody, a primer, a probe, a nucleic acid chip or a protein chip for assessing the risk of relapse after treatment of a patient suffering from depression, said assessment being an early diagnosis or an assisted diagnosis;
wherein the marker for risk of recurrence of depression comprises:
a protein selected from markers of M2: (M2) HIF-1 α; and
MRNA or protein of one or two markers selected from M1 and M3: (M1) HSP90; (M3) BICC1;
wherein the diagnostic reagent or kit is used for detecting the expression level of the risk marker in the sample to be detected, and the expression level of the risk marker is the expression level in serum;
And when the level C1 of the risk marker selected from the following group is significantly higher than the control reference value C0, then the test subject is prompted to have a high risk of relapse of depression:
A protein selected from markers of M2: (M2) HIF-1 α; and
MRNA or protein of one or two markers selected from M1 and M3: (M1) HSP90; (M3) BICC1;
And the control reference value C0 is the concentration of the risk marker in the same sample in a patient with no depression recurrence.
2. The use according to claim 1, wherein the sample to be tested is selected from the group consisting of: blood, plasma, serum, or a combination thereof.
3. The use of claim 1, wherein the kit further comprises a label or instructions for diagnosing the risk of recurrence after treatment of a patient suffering from depression.
4. A use according to claim 3, wherein the label or instruction indicates the following: if the transcript levels of HSP90 and BICC1 in said risk markers of the test subject are significantly higher than the control reference value, then the risk of recurrence of depression in the test subject is indicated to be higher than in normal depression patients.
5. A use according to claim 3, wherein the label or instruction indicates the following:
if the risk marker concentration C1 of the test subject is significantly higher than the control reference value C0, the subject has a greater chance of relapse depression than in a normal depression patient.
6. The use according to claim 1, wherein a lower risk of relapse of depression in the test subject is indicated if the level of translation of the risk marker in the test subject is not higher than a control reference value.
7. The use according to claim 1, wherein the ratio significantly higher than the ratio denoted C1/C0 is ≡1.5.
8. The use according to claim 1, wherein the ratio significantly higher than the ratio denoted C1/C0 is ≡2.
9. The use according to claim 1, wherein the ratio significantly higher than the ratio denoted C1/C0 is ≡3.
10. The use of claim 1, wherein an increased risk of recurrence of depression disorder in the subject is indicated if the amount of HSP90 protein or mRNA level is increased and the amount of HIF-1α protein is increased but the mRNA level of HIF-1α is not significantly changed or altered.
11. The use of claim 1, wherein an increased risk of recurrence of depression is indicated in the subject if the amount of protein of HSP90, HIF-1 a and BICC1 or the mRNA levels of HSP90 and BICC1 are increased.
12. A set of markers for predicting risk of relapse of depression, said set comprising 3 markers:
(M1) transcripts, or proteins, of HSP 90;
(M2) HIF-1 a protein; and
(M3) transcripts, or proteins, of BICC 1.
13. A depression recurrence risk assessment device, the device comprising:
(a) The input module is used for inputting depression recurrence risk marker data in serum of a certain detection object, and the detection object is a treated depression patient;
Wherein the risk marker gene comprises:
A protein selected from markers of M2: (M2) HIF-1 α; and
MRNA or protein of one or two markers selected from M1 and M3: (M1) HSP90; (M3) BICC1;
(b) A data processing module for processing depression recurrence risk marker data and giving a recurrence risk assessment value, wherein the processing comprises: comparing the level of the inputted marker C1 with a control reference value C0, wherein when C1 is significantly higher than C0, the subject is prompted to have a high risk of relapse of depression; when C1 is not significantly higher than C0, then suggesting that the subject has a low risk of relapse of depression; and
(C) The output module is used for outputting the evaluation result;
Wherein the control reference value C0 is the concentration of the risk marker in the same sample in a patient with no depression recurrence.
14. The apparatus of claim 13, wherein the ratio substantially higher than C1/C0 is ≡ 1.5.
15. The apparatus of claim 13, wherein the ratio substantially higher than C1/C0 is ≡2.
16. The apparatus of claim 13, wherein the ratio substantially higher than C1/C0 is ≡3.
17. The apparatus of claim 13, wherein the input module is further configured to input depression quantification scoring data based on the hamiltonian depression scale.
18. The apparatus of claim 13, further comprising a detection module for detecting transcript levels, protein levels, or protein activity of the risk marker.
19. The apparatus of claim 18, wherein the detection module is selected from the group consisting of: a PCR detector, a sequencer, or a combination thereof.
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