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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）是间质性肺病的最常见形式，是一种与极差预后相关的慢性进行性疾病。目前IPF无法治愈，治疗方案相对无效。IPF死亡继续增加，男性死亡率显著高于女性。动物研究数据也显示，男性更易患IPF。这些观察结果推断，性别可能在这种疾病的演变中起着重要作用。尽管进行了大量研究，但对IPF发病机制的了解仍然很少，很少有研究调查了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。使用诊断为不同严重程度IPF患者的肺组织（通过预测的FVC确定），我们将设计定制表达测定以同时测量47个基因靶标的转录谱，40已知在疾病发展和/或发病机制中重要，如动物和一些人类研究所示（非性别/纤维化基因）和7个性别相关基因，这些基因可能影响基因表达谱和疾病严重程度之间的性别依赖性关联。我们的总体假设是，性别将影响基因表达水平的一个子集的目标，这与疾病的严重程度。我们预期性别将影响与非性别相关基因表达相关的性别相关基因表达特征，并进一步影响疾病的严重程度。将在以下2个特定目标中检验该假设：（SA 1）测量诊断为不同严重程度IPF的患者肺组织样本中47种基因（性别相关和非性别相关/纤维化基因）的表达水平。为了实现这一目标，将开发定制QRT-PCR测定法，并测定每份肺样本的这些基因的表达水平。(SA2)开发和评价两阶段统计模型，以从47个基因（包括性别相关和非性别相关）中选择靶基因，确定非性别相关基因表达水平是否因IPF严重程度和性别而异，以及性别相关基因是否间接影响非性别相关基因表达水平。从这项工作中获得的信息将提供以下方面的宝贵信息：（1）哪些基因（包括性别和非性别相关基因）在人类患者中发生了改变;（2）性别的影响是否由激素受体信号传导对纤维化基因介导;（3）激素受体信号传导对IPF严重程度的影响是否由纤维化基因介导或与我们研究的纤维化基因无关。阐明驱动IPF相关关键基因表达的分子和细胞机制将有助于建立新的或改进的早期疾病生物标志物，并增强治疗早期肺部疾病的治疗和预后策略。 (End摘要）公共卫生关系：项目叙述：患有间质性肺病如肺纤维化的个体面临着有限的治疗选择，这些治疗选择相当无效。男性IPF的发病率和死亡率上升表明激素可能在疾病发生和进展中发挥作用。阐明可能导致IPF产生的分子机制将改善患者诊断和治疗，并建立内分泌系统与肺部疾病之间的关系。