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

描述(由申请人提供)：申请人致力于发展作为一名成功的内科科学家的职业生涯，并已制定了本提案中描述的职业发展计划，使他能够做到这一点。这一五年计划的核心部分是下文概述的研究项目。此外，申请人将受益于马克·彼得斯-戈尔德博士(小学)和布鲁斯·理查森博士(共同导师)的指导，这两位都是成就卓著的资深教授，在指导方面有着广泛和成功的记录。正式的课程、研讨会和参加会议都包括在这项计划中。密歇根大学现有的优秀研究和指导环境进一步加强了这一计划。特发性肺纤维化(IPF)是一种破坏性疾病，有效治疗方法有限。纤维异常增殖是其重要的病理生物学标志。前列腺素(PG)E2是一种脂质介质，能有效地抑制成纤维细胞，成纤维细胞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抑制具有抵抗力，这是由于E前列腺素(EP)2受体缺乏所致。这一发现与博莱霉素肺纤维化小鼠模型的观察结果相一致。目前尚不清楚EP2在这些细胞中的表达是如何丢失的。表观遗传变化是对DNA和染色质的共价修饰，在调节基因表达方面很重要，而且越来越多地被认为在疾病中具有重要作用。初步数据表明，表观遗传学机制可能是导致成纤维细胞EP2表达缺失和PGE2反应性受损的原因。为了验证这一假设，我们将研究来自细胞系、DIP患者和博莱霉素治疗的小鼠的肺成纤维细胞。我们的具体目标是探讨1)DMA甲基化和2)组蛋白去乙酰化在调节正常肺成纤维细胞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/或组蛋白去乙酰化可能如何与3)博莱霉素治疗的小鼠和4)IPF患者的成纤维细胞EP2缺乏/PGE2耐药有关。申请者将在其生产性培训经验的基础上获得新的科学知识和研究技能，特别是在表观遗传学领域，这一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发病机制提供新的见解，并为申请者提供在一个令人兴奋和重要的研究领域实现学术独立的技能。相关性(见说明)：特发性肺纤维化是一种严重的肺部疾病，预后差，治疗效果不佳。这项计划中提出的研究旨在更好地了解肺纤维化的发病机制，这可能会导致开发出针对这种致命疾病的更好的治疗策略。

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.