Epigenetic Regulation of the E Prostanoid 2 Receptor Gene in Lung Fibroblasts

肺成纤维细胞中 E 类前列腺素 2 受体基因的表观遗传调控

基本信息

批准号：
8241049
负责人：
STEVEN K HUANG
金额：
$ 13.37万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8241049
关键词：
Accounting Address Adult Alveolar Macrophages Area Attention Bleomycin Cell Line Cells Chromatin Collagen Commit Communities Critical Pathways DNA Methylation Data Deacetylation Defect Deposition Development Development Plans Diagnosis Dinoprostone Disease Disease Progression Dyspnea Effector Cell Elderly Environment Environmental Exposure Epigenetic Process Epithelial Cells Etiology Exhibits Extracellular Matrix Fetal Lung Fibroblasts Fibrosis Figs - dietary Five-Year Plans Functional disorder Future Gases Gene Expression Genes Hamman-Rich syndrome Histone Acetylation Histone Deacetylation Human Instruction Knowledge Lead Life Expectancy Lung Lung diseases Malignant Neoplasms Mediator of activation protein Mentors Mentorship Metabolism Methylation Michigan Modeling Modification Mus Neuroblastoma Organ Pathogenesis Pathologic Pathology Patients Pattern Physicians Physiology Play Principal Investigator Prostaglandin-Endoperoxide Synthase Prostaglandins Pulmonary Fibrosis Receptor Gene Records Regulation Research Research Project Grants Resistance Respiratory Failure Role Scientist Signal Transduction Symptoms Testing Therapeutic Time Training Transforming Growth Factors Universities base career career development effective therapy experience indium-bleomycin insight lipid mediator mouse model neoplastic cell outcome forecast professor prostaglandin EP2 receptor receptor receptor expression response skills symposium

项目摘要

DESCRIPTION (provided by applicant): The applicant is committed to developing a career as a successful physician-scientist and has created a career development plan described in this proposal that will allow him to do so. The central component of this five-year plan is the research project outlined below. In addition, the applicant will benefit from the mentorship of Dr. Marc Peters-Golden (primary) and Dr. Bruce Richardson (co-mentor), both accomplished senior professors with extensive and successful track records for mentoring. Formal coursework, seminars, and conference participation are included in this plan. This plan is further enhanced by the outstanding research and mentoring environment that exists at the University of Michigan. Idiopathic pulmonary fibrosis (IPF) is a devastating disease with limited effective therapies. Abnormal fibroproliferation is a key pathobiological hallmark. Prostaglandin (PG) E2 is a lipid mediator that potently inhibits fibroblasts, the main effector cell in fibrotic responses. The applicant has recently discovered that fibroblasts from some patients with IPF are resistant to PGE2 suppression, and that this is due to deficiency of the E prostanoid (EP) 2 receptor. This finding parallels observations made in the bleomycin mouse model of pulmonary fibrosis. What is unclear is how EP2 expression is lost in these cells. Epigenetic changes, which are covalent modifications to DMA and chromatin, are important in regulating gene expression, and are increasingly recognized to be important in disease. Preliminary data suggest that epigenetic mechanisms may be responsible for loss of EP2 expression and impaired PGE2 responsiveness in fibrotic fibroblasts. To test this hypothesis, we will study lung fibroblasts from cell lines, patients with DIP, and from mice treated with bleomycin. Our Specific Aims will be to address the role of 1) DMA methylation and 2) histone deacetylation in regulating EP2 receptor expression and PGE2 responses in normal lung fibroblasts. We will then study how DMA methylation and/or histone deacetylation may be responsible for EP2 deficiency/PGE2 resistance in fibroblasts from 3) bleomycin-treated mice and 4) patients with IPF. The applicant will build upon his productive training experience by acquiring new scientific knowledge and research skills, particularly in the area of epigenetics, a field that has generated significant enthusiasm within the scientific community. Successful completion of the outlined studies will provide new insight into pathogenic mechanisms of pulmonary fibrosis and provide the applicant with the skills to achieve academic independence in an exciting and important research niche. RELEVANCE (See instructions): Idiopathic pulmonary fibrosis is a devastating lung disease with a poor prognosis and little effective therapy. The research proposed in this plan seeks to better understand the pathogenesis of pulmonary fibrosis which may lead to the development of better therapeutic strategies against this deadly disease.

描述（由申请人提供）：申请人致力于发展成为一名成功的医师科学家的职业生涯，并制定了本提案中描述的职业发展计划，使他能够实现这一目标。该五年计划的核心组成部分是下述研究项目。此外，申请人还将受益于 Marc Peters-Golden 博士（初级）和 Bruce Richardson 博士（共同导师）的指导，他们都是资深教授，拥有广泛而成功的指导记录。该计划包括正式课程、研讨会和会议参与。密歇根大学出色的研究和指导环境进一步增强了该计划。特发性肺纤维化（IPF）是一种毁灭性的疾病，有效的治疗方法有限。纤维增殖异常是一个关键的病理生物学标志。前列腺素 (PG) E2 是一种脂质介质，可有效抑制成纤维细胞（纤维化反应中的主要效应细胞）。申请人最近发现，来自一些IPF患者的成纤维细胞对PGE 2 抑制具有抵抗力，这是由于E前列腺素(EP) 2 受体的缺乏。这一发现与博来霉素小鼠肺纤维化模型中的观察结果相似。目前还不清楚EP2 表达是如何在这些细胞中丢失的。表观遗传变化是 DMA 和染色质的共价修饰，对于调节基因表达非常重要，并且人们越来越认识到它在疾病中的重要性。初步数据表明，表观遗传机制可能是纤维化成纤维细胞中 EP2 表达缺失和 PGE2 反应性受损的原因。为了检验这一假设，我们将研究来自细胞系、DIP 患者和博莱霉素治疗小鼠的肺成纤维细胞。我们的具体目标是解决 1) DMA 甲基化和 2) 组蛋白脱乙酰化在调节正常肺成纤维细胞中 EP2 受体表达和 PGE2 反应中的作用。然后，我们将研究 DMA 甲基化和/或组蛋白脱乙酰化如何导致 3) 博莱霉素治疗小鼠和 4) IPF 患者成纤维细胞中的 EP2 缺乏/PGE2 耐药。申请人将通过获取新的科学知识和研究技能，特别是在表观遗传学领域，在其富有成效的培训经验的基础上，这一领域在科学界引起了极大的热情。成功完成上述研究将为肺纤维化的致病机制提供新的见解，并为申请人提供在令人兴奋且重要的研究领域实现学术独立的技能。相关性（参见说明）：特发性肺纤维化是一种毁灭性的肺部疾病，预后不良，且几乎没有有效的治疗方法。该计划提出的研究旨在更好地了解肺纤维化的发病机制，这可能有助于开发针对这种致命疾病的更好的治疗策略。