KR20170126320A - Novel Biomarker for Diagnosing Pulmonary Diseases and Uses Thereof - Google Patents

Abstract

The present invention relates to a novel biomarker for diagnosing pulmonary diseases and uses thereof, wherein as a biomarker of the present invention, folliculin can be used as a therapeutic target for treating asthma and an indicator capable of predicting and determining pulmonary diseases, particularly asthma. The present invention can help to categorize patients who can maximize the therapeutic effect of medicines or minimize the side effects, and enable more effective treatment.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel biomarker for diagnosing pulmonary disease,

The present invention relates to a novel biomarker for lung disease diagnosis and its use.

The lungs occupy 6% of the body's volume and promote systemic circulation and gas exchange. Thus, pulmonary disease resulting in loss of pulmonary function may be life-threatening.

The most commonly diagnosed lung diseases are emphysema, asthma, pneumonia, tuberculosis, pulmonary hypertension and lung cancer.

Among them, asthma is a reversible obstructive airway disease characterized by inflammatory changes, and symptoms such as seizure dyspnea, cough, and sputum due to reversible airway constriction. Bronchial smooth muscle contraction or seizures, bronchial mucosal edema and mucus secretion is caused by increased secretion of smooth muscle is the main mechanism. One of the most powerful theories known to cause airway constriction has been the inhalation and ingestion of antigens, which causes hypersensitivity of the airways, resulting in widespread airway constriction.

COPD (chronic obstructive pulmonary disease) is a term referring to a large group of lung diseases that can interfere with normal respiration. Current clinical guidelines define COPD as a disease state characterized by a non-reversible airflow limitation. Airflow limitation is generally progressive and is associated with an abnormal inflammatory response of the lungs to toxic particles and gases. The most important contributing source of these particles and gases is tobacco smoke. Patients with COPD exhibit a variety of symptoms including coughing, shortness of breath, and the generation of excessive sputum. These symptoms arise from dysfunctions of multiple cell compartments, including neutrophils, macrophages and epithelial cells. The two most important states included in COPD are chronic bronchitis and emphysema.

Chronic bronchitis is a persistent inflammation of the bronchi that causes increased mucus production and other changes. The symptoms of the patient are cough and sputum discharge. Chronic bronchitis can result in more frequent and severe respiratory infections, bronchial stenosis and blockage, dyspnea and respiratory failure.

Emphysema is a chronic lung disease affecting the alveoli and / or the minimal bronchial end. The lungs lose their elasticity, thereby expanding the area of the lungs. This extended area prevents the flow of fresh air and does not effectively exchange it with fresh air. This can lead to dyspnea, and oxygen can be delivered to the blood insufficiently. The prominent symptom in the model patient is shortness of breath.

In general, these lung diseases can not be diagnosed as diseases by simply breathing. In order to judge the occurrence of lung diseases, it is necessary to go through an expensive and precise examination procedure. Because of these inconveniences and burdens, most patients do not receive separate screenings to check for lung disease. Sometimes they feel uncomfortable in their lives, and often become worse when treatment is difficult.

In addition, there is an inconvenient problem that the patient needs to visit the hospital every day to go through a complicated examination procedure, although continuous monitoring is required after the lung disease is already found and treated.

Meanwhile, Folliculin (FLCN) is a cell binding protein, and its role as a tumor suppressor gene is known. In connection with policurin, studies have been conducted on diseases caused by mutation of policulin, for example, Birt-Hogg-Dube syndrome. However, studies on the relationship between policlin and lung disease are not known.

Under such circumstances, the inventors of the present invention have been studying a method for easily and rapidly diagnosing pulmonary disease. When the level of expression of policulin is analyzed as a specific lung disease-specific biomarker in serum of a subject, And / or can be easily and accurately diagnosed and / or monitored.

Accordingly, an object of the present invention is to provide a composition for diagnosing pulmonary disease or predicting prognosis.

Another object of the present invention is to provide a kit for lung disease diagnosis or prognosis prediction.

It is still another object of the present invention to provide a method for providing information for diagnosis or prognosis prediction of lung disease or lung function.

It is still another object of the present invention to provide a screening method for a therapeutic agent for lung disease.

Hereinafter, the present invention will be described in more detail.

According to one aspect of the present invention, the present invention provides a composition for predicting lung disease diagnosis or prognosis, which comprises an agent for measuring the expression level of mRNA of a folliculin (NM_144997.5) gene or a protein thereof.

As used herein, the term "diagnosis" refers to identifying the presence or characteristic of an individual or a pathological condition of a subject for a specific disease or disease, and refers to an individual for a specific disease or disease, Lt; RTI ID = 0.0 > currently < / RTI > For the purpose of the present invention, it is to confirm whether or not lung disease develops.

That is, since the lung disease is characterized by overexpression of the expression level of the policulin gene or protein, the mRNA expression level of the folliculin (FLCN) gene; Or when the level of expression or activity of the protein of the present invention is measured, it is diagnosed that the expression level of the policulin gene or protein is over-expressed (or highly expressed).

As used herein, the term "prognosis" is intended to include determining whether a subject for a particular disease or disorder, i.e., the subject to be tested, will have the disease later, determining the subject's responsiveness to treatment, (e. g., monitoring the condition of an individual to provide information about treatment efficacy).

That is, it means judging conditions such as recurrence, metastasis, drug reactivity, tolerance, lung function level, etc. of a subject after treatment of lung disease.

In the present invention, the mRNA expression level of the folliculin (FLCN) gene; Or by measuring the level of expression or activity of the protein of the present invention, it is possible to predict not only the incidence of the lung disease of the individual, but also the lung function level and lung disease prognosis of the individual.

According to a preferred embodiment of the present invention, the pulmonary disease is selected from the group consisting of asthma, emphysema, pneumonia, tuberculosis, pulmonary hypertension, lung cancer, neonatal bronchopulmonary dysphoria, chronic obstructive pulmonary disease, acute bronchitis, chronic bronchitis, bronchiectasis, Acute respiratory distress syndrome, acute lung injury, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, acute respiratory distress syndrome, acute respiratory distress syndrome, acute respiratory distress syndrome, , And more preferably at least one kind selected from the group consisting of asthma, emphysema, pneumonia, tuberculosis, pulmonary hypertension and lung cancer, and most preferably asthma.

The term "overexpression" or "high expression " used to express the over-expressing pulmonary disease of the present invention is meant to indicate that when the level of expression of poluculin is measured by a suitable expression assay, (For example, the normal cells of the relevant organ).

In the present invention, preferably the poluculin high expression may be a policulin level of 10 pg / ml to 1000 pg / ml in serum, more preferably 100 pg / ml to 800 pg / ml, even more preferably 100 pg / ml To 500 pg / ml, and most preferably 100 pg / ml to 200 pg / ml.

As used herein, the expression "expression level of a gene, or measurement of its expression level ", as used herein, means to detect a target to be detected in the sample.

In the present invention, the target to be detected is the mRNA and / or protein of the corresponding gene in the sample. That is, the expression level and / or the level of expression of the gene can be confirmed by detecting RNA, which is a transcription product of the target, or protein as a gene product.

Detection of RNA or protein can usually be performed by extracting RNA or protein from the sample and detecting RNA or protein in the extract. The detection of such RNA or protein can be measured by immunoassay, hybridization and amplification reactions, but is not limited thereto and can be easily carried out using various techniques known in the art.

According to a preferred embodiment of the present invention, the agent for measuring the mRNA expression level of the gene may comprise a primer pair, a probe or an antisense nucleotide which specifically binds to a policulin gene.

That is, the detection of the nucleic acid can be performed by an amplification reaction using a nucleic acid molecule encoding the gene or one or more oligonucleotide primers hybridized to the nucleic acid molecule.

For example, the detection of mRNA using a primer can be performed by amplifying the gene sequence using an amplification method such as PCR, and then confirming amplification by a method known in the art.

The term "probe" means a nucleic acid fragment such as RNA or DNA corresponding to a few nucleotides or several hundreds of nucleotides that can specifically bind to an mRNA, and is labeled to confirm the presence or expression level of a specific mRNA . The probe may be prepared in the form of an oligonucleotide probe, a single strand DNA probe, a double strand DNA probe, or an RNA probe. Selection of suitable probes and hybridization conditions can be appropriately selected according to techniques known in the art.

The term "primer" refers to a nucleic acid sequence having a short free 3 'hydroxyl group and capable of forming a base pair with a complementary template and having a short nucleic acid sequence serving as a starting point for template strand copying It says. Primers can initiate DNA synthesis in the presence of reagents for polymerization (i. E., DNA polymerase or reverse transcriptase) and four different nucleoside triphosphates at appropriate buffer solutions and temperatures. The PCR conditions, the lengths of the sense and antisense primers can be appropriately selected according to techniques known in the art.

According to a preferred embodiment of the present invention, the agent for measuring the expression level of the protein comprises an antibody, an interaction protein, a ligand, a nanoparticle or an aptamer that specifically binds to the protein or peptide fragment, . ≪ / RTI >

In the present invention, the agent for measuring the expression level of the protein refers to an antibody that specifically binds to the protein, and includes both a polyclonal antibody, a monoclonal antibody, a recombinant antibody, and a combination thereof.

Such antibodies include both full forms with polyclonal antibodies, monoclonal antibodies, recombinant antibodies and two full-length light chains and two full-length heavy chains as well as functional fragments of antibody molecules, such as Fab, F (ab ' ), F (ab ') 2, and Fv. Antibody production can be easily performed using techniques well known in the art to which the present invention is applicable, and commercially produced antibodies can be used.

The composition of the present invention can be used not only as a preparation for measuring the expression of the gene described above but also as a label for quantitatively or qualitatively measuring the formation of an antigen-antibody complex, a common tool and reagent used for immunological analysis .

Labels that enable qualitative or quantitative measurement of the formation of antigen-antibody complexes include, but are not necessarily limited to, enzymes, minerals, ligands, emitters, microparticles, redox molecules, and radioisotopes . Enzymes that can be used as detection labels include, but are not limited to,? -Glucuronidase,? -D-glucosidase,? -D-galactosidase, urease, peroxidase, alkaline phosphatase, acetylcholinesterase, A prodrug thereof, a prodrug thereof, a prodrug, a hexose kinase, a GDPase, an RNase, a glucose oxidase and a luciferase, a phosphofructokutase, a phosphoenolpyruvate carboxylase, an aspartate aminotransferase, a phosphoenolpyruvate decarboxylase, ≪ RTI ID = 0.0 > Ratama < / RTI > The minerals include, but are not limited to, fluorescein, isothiocyanate, rhodamine, picoeriterine, picocyanin, allophycocyanin, o-phthaldehyde, fluororescamine and the like. Ligands include, but are not limited to, biotin derivatives. Emitters include, but are not limited to, acridinium esters, luciferin, luciferase, and the like. Fine particles include, but are not limited to, colloidal gold, colored latex, and the like. Redox molecules include ferrocene, ruthenium complex compounds, Biology hydrogen, quinone, Ti ions, Cs ions, diimide, 1,4-benzoquinone, ^{_{hydroquinone, K 4 W (CN) 8}} , [Os (bpy) 3] 2+ , [RU (bpy) ₃ ] ²⁺ , [MO (CN) ₈ ] ^4-, and the like. Radioisotopes include include ^{3 H, 14 C, 32 P} , 35 S, 36 Cl, 51 Cr, 57 Co, 58 Co, 59 Fe, 90 Y, 125 I, 13 1I, 186 Re , and without limitation.

Examples of such tools or reagents include, but are not limited to, suitable carriers, solubilizers, cleaning agents, buffers, stabilizers, and the like. When the labeling substance is an enzyme, it may include a substrate capable of measuring enzyme activity and a reaction terminator. Examples of the insoluble carrier include polystyrene, polyethylene, polypropylene, polyester, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, Acrylonitrile, fluororesin, crosslinked dextran, polysaccharide, other paper, glass, metal, agarose, and combinations thereof.

According to another aspect of the present invention, there is provided a kit for analyzing a lung disease diagnosis or prognosis, which comprises the above composition.

The kit may be various types of kits depending on the method to be used, including, for example, a microarray, a gene amplification kit, or a kit for immunoassay.

The kit may include expression of the gene; Or an agent for measuring the expression level of the protein of the present invention, as well as tools, reagents and the like commonly used in the art used for immunological analysis.

Examples of such tools or reagents include, but are not limited to, suitable carriers, markers capable of generating detectable signals, chromophores, solubilizers, buffers, stabilizers, and the like. When the labeling substance is an enzyme, it may include a substrate capable of measuring enzyme activity and a reaction terminator. Examples of the insoluble carrier include polystyrene, polyethylene, polypropylene, polyester, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, Acrylonitrile, fluorine resin, crosslinked dextran, polysaccharide, polymer such as magnetic fine particles plated with metal on latex, other paper, glass, metal, agarose and combinations thereof.

Since the kit of the present invention includes the above-described composition as a constituent, redundant contents are omitted in order to avoid excessive complexity of the present specification.

According to another aspect of the present invention, the present invention relates to a method for diagnosing lung disease or pulmonary function, comprising measuring the expression level of mRNA of the folliculin (NM_144997.5) gene or a protein thereof in a biological sample separated from the subject And provides information for diagnosis or prediction of prognosis.

The method further comprises comparing the expression level of the mRNA of the gene of the step or of the protein of the step with the control sample.

According to a preferred embodiment of the present invention, after obtaining a biological sample from a subject and measuring the level of expression of the gene or protein present in the biological sample, .

That is, mRNA expression level of the folliculin (FLCN) gene of the subject; Or when the expression level or activity level of the protein is measured, it is diagnosed that the policlin gene or protein is expressed as an over-expression level relative to a normal individual, thereby diagnosing the lung disease.

In addition, the present invention can diagnose pulmonary function levels according to the level of expression of said gene or protein present in said biological sample.

In the present invention, the predicted values of Pre BD FEV 1%, FVC%, FEV 1 / FVC and post BD FEV 1% were lower as the policlin level was higher. These values are lower in severe asthma patients.

That is, the lower the pulmonary function, the lower the pulmonary function index value, and the higher the expression pattern of policurin.

Thus, mRNA expression levels of the folliculin (FLCN) gene of the subject; Or the expression level or activity level of the protein is determined to be overexpressed relative to the normal individual, asthma severity can be determined as well as diagnosis of lung function depression.

The "control" is the level of expression of the gene of interest or its protein in a normal healthy person; Or the level of expression of the gene of interest or its protein in the subject to be compared.

Also, terms used in referring to the expression level of the gene as a biomarker are referred to as having a " differential level "or" differential value " or "differentially expressed" And includes both qualitative as well as quantitative differences in expression.

The term "biological sample" as used herein means all samples obtained from an individual from which expression of the gene or protein of the present invention can be detected.

The biological sample is any one selected from the group consisting of whole blood, serum, plasma, alveolar lavage fluid, sputum, lung tissue, saliva, biopsy, liquid culture, feces and urine, And can be prepared by treatment with a method commonly used in the technical field of the present invention.

The method of the present invention determines the pulmonary disease using the expression level of the above-mentioned gene or protein, so redundant contents are omitted in order to avoid the excessive complexity of the present specification.

According to another aspect of the present invention, the present invention provides a method for screening a therapeutic agent for a pulmonary disease, comprising the steps of:

(a) contacting a candidate substance to a sample isolated from a lung disease patient comprising mRNA of the folliculin (NM_144997.5) gene or a protein thereof; And

(b) measuring a change in the expression level of mRNA of the gene or a protein thereof.

According to a preferred embodiment of the present invention, when the expression level of the gene mRNA or protein in the step (b) is decreased as compared with that before the candidate substance is contacted, the step of determining the candidate substance as a therapeutic agent for pulmonary disease.

Specifically, policulin can be useful for screening therapeutic agents by comparing the increase or decrease of expression of policulin in the presence and absence (before and after treatment) of lung disease therapeutic candidates. Substances that reduce the level of policurine indirectly or directly can be selected as therapeutic agents for pulmonary diseases.

That is, the level of expression of the policulin of the present invention in the sample disclosed in the present invention in the absence of the cancer treatment candidate substance (before treatment) is measured, and the level of expression of the poluculin of the present invention In the absence of a candidate for a therapeutic agent for pulmonary disease, a substance which reduces the expression level of the marker of the present invention in the presence of a candidate for lung disease treatment, compared with the expression level of the marker in the absence of a lung disease therapeutic candidate substance, It can be predicted as a treatment for lung disease.

The candidate substance can be used to express the gene of the present invention; Or an inhibitor that inhibits expression or activity of the protein of the gene.

The inhibitor may be selected from the group consisting of siRNA (small interference RNA), shRNA (short hairpin RNA), miRNA (microRNA), ribozyme, DNAzyme, peptide nucleic acids, antisense oligonucleotides, antibodies, aptamers, And at least one selected from the group consisting of materials.

The method of the present invention determines the therapeutic agent using the level of expression of the gene described above, so redundant descriptions are omitted to avoid undue complexity of the present disclosure.

As a biomarker of the present invention, policulin can be used as a therapeutic target for treating asthma and asthma, which can predict and judge lung diseases, particularly asthma. This can help to classify patients who can maximize the therapeutic effect of medicines or minimize side effects and enable more effective treatment.

Figure 1 shows the difference in serum folliculin levels between asthmatic and normal subjects.
Figure 2 shows the difference in serum policurin levels according to pulmonary function.
Figure 3 shows the difference in policurin levels according to pulmonary function index and related index analysis.
Fig. 4 shows the difference in the level of policlin according to the age, smoking habit, and acute exacerbation level at 3-month intervals for each group in each group.
Fig. 5 shows the difference in the level of policurin according to the lung function maintenance trend analysis.
Fig. 6 shows the ROC curve of the policlin in the serum.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the invention as defined by the appended claims. It will be obvious to you.

Example  1. Experimental Method

1-1. Subject

A total of 404 asthmatic patients who participated in the prospective, species, and multicenter studies of Korean patients with asthma were enrolled and reviewed retrospectively from January 2005 to May 2014 by visiting the asthma clinic at Asan Medical Center. Reversible airway obstruction with symptoms including intermittent cough and dyspnea lasting more than 3 months and a positive bronchodilator response [> 12% improvement in FEV1 (forced expiratory volume in 1 s) after 180 mg of albuterol] Based on the criteria set forth by the Global Initiative for Asthma (GINA), which represents evidence of a bronchial hyperresponsiveness (a metacholine spiked concentration resulting in a 20% reduction in FEV1 ≤16 ㎎ / ㎖) indicative of a positive methacholine challenge And the diagnosis of asthma was made. Registered asthmatic patients were in a stable state treated with the assigned drugs assessed by the GINA guidelines. Simple chest X - ray and bronchial dilatation were excluded. The patient visited the outpatient clinic regularly every 3 months (SD, 30 days). At all visits, allergy specialists adjusted the patient's medication according to current asthma control status and investigated the occurrence of asthma exacerbations during the last three months. As a healthy control group, 94 patients who visited the health promotion center of the same hospital were recruited.

We have defined asthma exacerbations according to the definition of the official American Thoracic Society / European Respiratory Society policy (severe asthma exacerbation) which includes at least one of the following: (1) the use of any type of systemic corticosteroid or a minimum of 3 And / or (2) hospitalization and emergency room visitation power due to asthma requiring additional systemic corticosteroids.

The variables were measured at baseline, including the population, smoking, body mass index (BMI), frequency of deterioration for one year, laboratory values, PC20, and bronchodilator - Respectively. This study was approved by the Asan Medical Center clinical trial committee.

1-2. Measure

Serum folliculin levels in asthmatic patients (n = 404) and normal controls (n = 94) were measured by a commercially available ELISA kit (CUSABIO, CSB-EL008711HU) according to the manufacturer's recommendations. Demographic and clinical data were collected from the participants' evaluation criteria for each study. The levels of policurin between the two groups were compared and the present inventors investigated when the level of policurin correlated with pulmonary function and other clinical variables within the asthmatic group. The policulin high expression group was defined as a patient with a policurin level of 148 pg / ml or higher (mean log value of 4.8 or higher), and the inventors also sought to identify the clinical characteristics of the 'policulin high expression' phenotype.

1-3. Statistical analysis

All statistical analyzes were performed using SPSS 12.0 (SPSS, Inc. Chicago, Illinois). The Kolmogorov-Smirnov test assessed the normal distribution. Comparisons between groups were performed with one-way analysis of variance and Student's t test. Categorical variables were analyzed by Fisher's exact test and chi-square test. Correlations of the normal distribution data were evaluated by Pearson and Spearman tests respectively.

Experimental Example  1. In serum Policulin  Diagnosis of pulmonary disease according to level

The present inventors confirmed the difference in serum folliculin levels between asthmatic and normal subjects.

As a result, as shown in Fig. 1, the serum concentration of policurin was significantly higher in asthmatic patients (148.92 ± 240.71 vs 73.57 ± 78.34 pg / ml, p <0.001) than the normal control group. That is, the level of policlin in the serum of the asthmatic and normal subjects was about twice as high as that of the asthmatic patients.

In order to adjust the level of policulin in the serum to the normal distribution, log value is symmetrical about the mean, and there is almost no reason why it is assumed that the normal distribution is less than 500.

For more accurate diagnosis, we adjusted the parameters such as age and smoking habits of asthmatic and normal subjects, and then compared the levels of serum policurin between asthmatic and normal subjects.

As a result, it was confirmed that the policlin was found to be about 2 times higher in the asthmatic group than the asthmatic group after age and smoking power correction.

In addition, the correlations with various variables showed that the higher the age, the higher the smoking, the higher the frequency of exacerbations, the higher the level of policlin in asthmatic patients.

According to the above results, serum policurin levels were significantly different between normal and asthmatic patients, and after age and smoking power correction, they were higher in asthmatic patients than normal subjects. Therefore, asthma was widely diagnosed in patients of various ages and smoking habits .

Experimental Example  2. Serum Policulin  Diagnosis of pulmonary function by level

2.1 Identification of Serum Policulin Levels by Pulmonary Function

The present inventors have confirmed the difference in serum policurin levels according to pulmonary function in order to confirm whether serum policulins can reflect the level of pulmonary function. Serum policlin levels were compared between normal subjects (n = 94) and asthmatic patients. Pre-BD FEV1 (%)> 80 (%) according to FEV1 for 1 second before bronchodilator treatment (n = 140), Pre BD FEV1 (%) 60 to 80 (n = 140), and Pre BD (%) FEV1 <60 (n = 124). Serum policlin was measured in 4 groups and the results are shown in Fig. Serum policlin was expressed by taking the log value.

As shown in FIG. 2, the control group had a low policlin level of 4.13, but the asthmatic patients showed a high policlin level of 4.74 or higher in all, and the higher the policlin level in severe asthmatic patients with lower FEV1 values It was confirmed that the more the pulmonary function was poor, the higher the expression tendency of policule. These results suggest that policulin can be used as a marker to diagnose not only asthma but also lung function and asthma severity.

2.2 Analysis of pulmonary function index and related index according to policurin level

As confirmed in Experimental Example 2.1, it was confirmed that policylin levels could be used as markers of pulmonary function. Therefore, the inventors of the present invention found that the policlin levels of asthmatic patients were higher than those of high-expression policulin groups (n = The prevalence of pre-BD FEV1%, FVC%, FEV1 / FVC, and post BD FEV1% predicted values of pulmonary function in the experimental group and PC20 And whether they can reflect significant differences.

As a result, as shown in Fig. 3, Pre BD FEV 1% and FVC%, FEV 1 / FVC and post BD FEV 1% with high expression of polyketide were found to be low values. These results indicate that the high folliculi of policulin can reflect a decrease in pulmonary function

The age, smoking habits, and acute exacerbations at 3-month intervals were compared.

As a result, as shown in Fig. 4, the high-expression-policulin group exhibited a higher incidence of asthma in the elderly than the low-expression policulin group, Respectively.

In particular, it was confirmed that acute exacerbation was observed at 3-month intervals. As a result, the high-expression-policurin group showed a high value of 0.55 as compared with the low-expression policurin group, indicating that the frequency of steroid administration was much higher due to acute exacerbation.

Therefore, it can be confirmed that asthma is highly likely to be exacerbated in a patient having a high expression level of 4.8 or more. Thus, it is possible to diagnose asthmatic patients having a possibility of acute exacerbation by measuring the level of policurin.

2.3 Analysis of pulmonary function maintenance according to policurin level

The present inventors classify the patient group into three groups using the trajectory model using the one-year time-lapse data in the patient group to analyze the maintenance of the lung function according to the policulin level, and the lung function is consistently good And group 3, which consistently showed poor pulmonary function, were group 1, and the levels of FEV1% and FEV1 / FVC were compared.

As a result, as shown in Fig. 5, a significant difference in the level of policurin between the respective groups was confirmed. These results suggest that policulin can be used as a marker for diagnosing not only asthma but also pulmonary function maintenance.

In addition, as shown in FIG. 6, the AUC on the ROC curve was appropriately classified as 84.6%, and significant p-value was shown. Also, the confidence interval was 0.5 or more in all the upper and lower limits, and the serum policlin was 74.45 pg / ml, sensitivity was 83.91% and specificity was 77.66%.

These results indicate that the serum concentration of policurin is higher in asthmatic patients, which is associated with decreased lung function. Therefore, policulin may be a new biomarker capable of diagnosing asthma, diagnosing severe asthmatic patients among asthmatic patients, confirming pulmonary function, and confirming acute exacerbation.

Claims (10)

A composition for predicting lung disease diagnosis or prognosis, which comprises an agent for measuring an expression level of mRNA of a folliculin (NM_144997.5) gene or a protein thereof.
The method of claim 1, wherein the pulmonary disease is selected from the group consisting of asthma, emphysema, pneumonia, tuberculosis, lung hypertension, lung cancer, neonatal bronchopneumonia, chronic obstructive pulmonary disease, acute bronchitis, chronic bronchitis, bronchiolitis, Acute respiratory distress syndrome, acute lung injury, idiopathic respiratory distress syndrome, and idiopathic pulmonary fibrosis, acute respiratory distress syndrome, acute lung injury, thermal lung injury, cystic fibrosis, Wherein the composition is at least one selected from the group consisting of:
The composition according to claim 1, wherein the agent for measuring mRNA expression level of the gene is a primer pair, a probe, or an antisense nucleotide that specifically binds to the policulin gene.
The method according to claim 1, wherein the agent for measuring the expression level of the protein is an antibody, an interaction protein, a ligand, a nanoparticle or an aptamer that specifically binds to the protein or peptide fragment .
A kit for diagnosing or prognosing a pulmonary disease comprising the composition according to any one of claims 1 to 4.
6. The kit according to claim 5, wherein the kit is a microarray, a gene amplification kit or an immunoassay kit.
Comprising measuring the expression level of mRNA of the folliculin (NM_144997.5) gene or a protein thereof in a biological sample separated from the subject, for the diagnosis or prognosis prediction of pulmonary disease or pulmonary function.
8. The method of claim 7, wherein the method comprises determining that the lung disease is onset or progression if the level of expression of the gene or protein present in the biological sample is increased relative to a normal subject.
(a) contacting a candidate substance to a sample isolated from a lung disease patient comprising mRNA of the folliculin (NM_144997.5) gene or a protein thereof; And (b) measuring a change in the expression level of mRNA of the gene or a protein thereof.
[10] The method of claim 9, wherein when the expression level of the mRNA or protein of the gene is decreased in comparison with that before contacting the candidate substance, the candidate substance is determined to be a therapeutic agent for pulmonary disease Way.

Images