The Influence of Gender on Molecular Signatures of Fibrotic Lung Disease

性别对纤维化肺病分子特征的影响

基本信息

批准号：
7690831
负责人：
Tara L Sabo-Attwood
金额：
$ 7万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-19 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7690831
关键词：
Affect Alzheimer&apos s Disease Animals Area Asthma Binding Bioinformatics Biological Assay Biological Markers Cessation of life Chronic Custom Development Diagnosis Diagnostic Disease Disease Progression Endocrine Endocrine system Environment Enzymes Epidemiologist Estrogens Evaluation Evolution Extracellular Matrix Female Gender Gender Role Gene Expression Gene Expression Profile Gene Targeting Genes Goals Gonadal Steroid Hormones Hamman-Rich syndrome Homeostasis Hormonal Hormones Human Immune system Incidence Individual Inflammation Interstitial Lung Diseases Investigation Lead Logistic Regressions Lung Lung diseases Measurement Measures Mediating Methods Modeling Molecular Molecular Profiling Molecular Target Nuclear Hormone Receptors Osteoporosis Pathogenesis Patients Pattern Play Process Production Prostate Pulmonary Fibrosis Receptor Signaling Research Role Sampling Severities Severity of illness Sex Characteristics Sex Preselection Signal Pathway Staging Statistical Models Steroids Structure of parenchyma of lung Testing Therapeutic Time Tissue Sample Tissues Transcript Woman Work abstracting animal data density design effective therapy experience gene interaction improved interest male malignant breast neoplasm men model development mortality novel strategies outcome forecast prognostic public health relevance reproductive sex steroid hormone steroid metabolism therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF), the most common form of interstitial lung disease, is a chronic progressive disorder associated with extremely poor prognosis. There is currently no cure for IPF, and treatment options are relatively ineffective. Death from IPF continues to increase, with mortality rates significantly higher in men than women. Data from animal studies also reveal males are more susceptible to IPF. These observations infer that gender likely plays a significant role in the evolution of this disease. Despite research efforts, mechanisms underlying the pathogenesis of IPF are poorly understood and few studies have investigated the role of hormones and hormonal signaling pathways in IPF. The overall goal of this proposal is to determine the relationship between gene expression changes and disease severity and gender. Using lung tissues from patients diagnosed with IPF of varying severity (determined by FVC predicted), we will design a custom expression assay to measure the transcriptional profile of 47 gene targets simultaneously, 40 known to be important in disease development and/or pathogenesis as shown in animal and some human studies (non-sex/fibrotic genes) and 7 sex-related genes that may influence a gender-dependent association between gene expression profiles and severity of disease. Our overall hypothesis is that gender will influence gene expression levels for a subset of targets which vary with disease severity. We expect gender will influence sex-related gene expression signatures which are associated with non sex-related gene expression and further affect disease severity status. This hypothesis will be tested in the following 2 specific aims; (SA1) To measure the expression levels of 47 genes (sex-related and non sex-related/fibrotic genes) in lung tissue samples of patients diagnosed with IPF of various severity. To complete this aim, custom QRT-PCR assays will be developed and expression levels of these genes will be determined for each lung sample. (SA2) To develop and evaluate a two-stage statistical model to select target genes from 47 genes including sex-related and non sex-related, determine whether non-sex related gene expression levels vary by severity of IPF and gender, and further, whether sex-related genes indirectly affect non-sex related gene expression levels. Information gained form this work will provide invaluable information on (1) which genes, both sex and non sex-related, are altered in human patients; (2) Whether the effect of gender is mediated by hormonal receptor signaling on fibrotic genes; (3) Whether the effect of hormonal receptor signaling on IPF severity is mediated by fibrotic genes or is independent of the fibrotic genes that we investigate. Clarification of the molecular and cellular mechanisms that drive expression of critical genes involved in IPF will aid in establishing new or improved early disease biomarkers and enhancing therapeutic and prognostic strategies to treat incipient lung disease. (End of Abstract) PUBLIC HEALTH RELEVANCE: Project Narrative: Individuals with interstitial lung disease such as pulmonary fibrosis are faced with limited treatment options that are rather ineffective. The rising incidence and mortality of IPF in males suggests hormones may play a role in disease development and progression. Elucidation of the molecular mechanisms that may contribute to the production of IPF will lead to improved patient diagnostics and therapeutics as well as establishing relationships between the endocrine system and lung disease.

描述（由申请人提供）：特发性肺纤维化（IPF）是间质性肺部疾病的最常见形式，是一种与预后极不良相关的慢性进行性疾病。目前无法治愈IPF，治疗方案相对无效。 IPF的死亡继续增加，男性的死亡率明显高于女性。来自动物研究的数据还表明，男性更容易受到IPF的影响。这些观察结果推断，性别可能在该疾病的进化中起着重要作用。尽管进行了研究工作，但IPF发病机理的基础机制知之甚少，很少有研究研究激素和激素信号通路在IPF中的作用。该提案的总体目标是确定基因表达变化与疾病严重程度和性别之间的关系。使用从严重程度不同的患者的肺组织（由FVC预测），我们将设计一种自定义表达测定法，以同时测量47个基因靶标的转录谱，40个已知在疾病发育和/或发病机理中很重要，如动物和某些人类研究（非性别 - 纤维化基因）的构造（非性别范围）的构成，该概念的构成可能性依赖性（非性质）的结合，其构造的构成依从性，并且具有性能扩展的构造性既定性均具有生态 - 疾病。我们的总体假设是，性别将影响因疾病严重程度而变化的靶标子集的基因表达水平。我们预计性别会影响与性别相关的基因表达特征，这些基因表达特征与非性别相关的基因表达相关并进一步影响疾病的严重程度状况。该假设将在以下两个特定目标中进行检验。（SA1）测量在诊断出患有各种严重程度IPF的患者的肺组织样本中，47个基因（与性别相关/与性别相关/纤维化基因）的表达水平。为了完成此目标，将开发自定义QRT-PCR分析，并确定每个肺样本的这些基因的表达水平。（SA2）开发和评估一个两阶段的统计模型，从47个基因中选择靶基因，包括与性别相关和非性别相关的基因，确定非性别相关的基因表达水平是否因IPF和性别的严重程度而变化，以及与性别相关的基因是否间接影响非性基因相关的基因表达水平。获得的信息这项工作将提供有关（1）的宝贵信息，该基因在人类患者中都会改变哪些基因和与性别有关的基因；（2）性别的作用是否是由激素受体信号传导对纤维化基因介导的；（3）激素受体信号传导对IPF严重程度的影响是由纤维化基因介导的还是与我们研究的纤维化基因无关。阐明推动IPF关键基因表达表达的分子和细胞机制将有助于建立新的或改善的早期疾病生物标志物，并增强治疗和预后策略以治疗初期的肺部疾病。（抽象的结尾）公共卫生相关性：项目叙述：肺纤维化等间质肺疾病的人面临的治疗方案有限，而治疗方案相当无效。 IPF在男性中的发病率和死亡率上升表明，激素可能在疾病发展和进展中起作用。阐明可能有助于产生IPF的分子机制将导致改善患者诊断和治疗疗法，并建立内分泌系统与肺部疾病之间的关系。