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

• 批准号: 8449679
• 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
• 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/8449679
• 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

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）：申请人致力于发展作为成功的医师科学家的职业，并制定了本提案中描述的职业发展计划，这将使他能够这样做。该五年计划的核心部分是以下概述的研究项目。此外，申请人将从Marc Peters-Golden博士（小学）和Bruce Richardson博士（Co-Incertor）的指导中受益，他们都是有成就的高级教授，拥有广泛而成功的指导记录。本计划包括正式的课程，研讨会和会议参与。密歇根大学存在的杰出研究和指导环境进一步增强了该计划。特发性肺纤维化（IPF）是一种毁灭性疾病，有效疗法有限。异常纤维化散析是关键的病理学标志。前列腺素（PG）E2是一种脂质介质，可有效抑制成纤维细胞，这是纤维化反应中的主要效应细胞。申请人最近发现，一些IPF患者的成纤维细胞对PGE2抑制具有抗性，这是由于E前列腺素（EP）2受体的缺乏。这一发现在肺纤维化的博来霉素小鼠模型中进行了相似之处。尚不清楚这些细胞中EP2表达如何丢失。表观遗传变化是对DMA和染色质的共价修饰，在调节基因表达方面很重要，并且越来越多地被认为对疾病很重要。初步数据表明，表观遗传机制可能导致EP2表达的丧失和纤维细胞中PGE2反应性受损。为了检验这一假设，我们将研究细胞系，浸入患者以及用博来霉素治疗的小鼠的肺成纤维细胞。我们的具体目的是解决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/或组蛋白脱乙酰基如何负责来自3）BLEOMYCIN处理的小鼠的成纤维细胞中EP2缺乏/PGE2耐药性和4）IPF患者。申请人将通过获得新的科学知识和研究技能，尤其是在表观遗传学领域的领域，以他的生产培训经验为基础，该领域在科学界引起了极大的热情。成功完成概述的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而重要的研究利基市场中实现学术独立性的技能。相关性（请参阅说明）：特发性肺纤维化是一种毁灭性的肺部疾病，预后较差且有效的治疗很少。该计划中提出的研究旨在更好地了解肺纤维化的发病机理，这可能导致针对这种致命疾病的更好的治疗策略发展。

项目成果

Histone modifications are responsible for decreased Fas expression and apoptosis resistance in fibrotic lung fibroblasts.

• DOI: 10.1038/cddis.2013.146
• 发表时间: 2013-05-02
• 期刊: CELL DEATH & DISEASE
• 影响因子: 9
• 作者: Huang, S. K.;Scruggs, A. M.;Donaghy, J.;Horowitz, J. C.;Zaslona, Z.;Przybranowski, S.;White, E. S.;Peters-Golden, M.
• 通讯作者: Peters-Golden, M.