Epigenetic regulation of intestinal homeostasis

描述（由申请人提供）：炎症性肠病（IBD）是一种多因素疾病，是一项重大的公共卫生挑战。了解IBD发病机制中的细胞和分子机制对于确定易感因素和设计新的靶向治疗方法至关重要。肠上皮细胞（IECs）与IBD的发病机制密切相关。尽管IEC提供了一种必要的屏障，并且在调节肠道微环境中的免疫细胞方面至关重要，但调节IEC功能的潜在分子机制尚未阐明。与表观遗传调控在IBD中的核心作用一致，有希望的研究已经确定组蛋白去乙酰化酶（HDAC）抑制剂作为治疗肠道炎症的推定疗法，但HDAC在肠道健康和疾病中的意义仍然知之甚少。本提案中概述的研究将通过定义iec -内在HDAC3的功能，直接测试表观遗传学在肠道稳态中的作用。采用两种新开发的突变小鼠品系和已建立的小鼠肠道炎症模型，本项目的两个具体目标将确定(i) IEC-intrinsic HDAC3表达对IEC稳态和粘膜屏障功能的影响，（ii） IEC-intrinsic HDAC3如何调节肠道炎症和修复的发生和进展。描述HDAC3对IEC稳态和肠道疾病的贡献将显著扩展我们对IBD相关分子机制的理解，并可能影响和证明开发更具选择性的HDAC抑制剂作为治疗方法。在我作为兽医病理学家的培训中，我发现我对上皮再生，粘膜免疫学和慢性肠道炎症的发病机制有浓厚的兴趣。因此，我与David Artis博士一起发起了这个项目，这个项目将基于我在表观遗传学和转录调控方面的知识，使我能够过渡到粘膜免疫学领域。我的论文工作为我提供了良好的表观遗传调控基础，但我之前没有接触过免疫学技术和肠道疾病模型。阿蒂斯实验室和宾夕法尼亚大学提供了一个特殊的科学和知识环境，使我能够利用现代，

DESCRIPTION (provided by applicant): Inflammatory bowel diseases (IBD) are multifactorial disorders that represent a significant public health challenge. Understanding the cellular and molecular mechanisms involved in the pathogenesis of IBD will be critical to the identification of predisposing factors and the design of novel, targeted therapeutics. Intestinal epithelial cells (IECs) have been strongly implicated in the pathogenesis of IBD. Although IECs provide an essential barrier and are crucial in regulating immune cells in the intestinal microenvironment, the underlying molecular mechanisms that regulate IEC function have not been elucidated. Consistent with a central role for epigenetic regulation in IBD, promising studies have identified histone deacetylase (HDAC) inhibitors as putative therapeutics for the treatment of intestinal inflammation, but the significance of HDACs in intestinal health and disease remains poorly understood. Studies outlined in this proposal will directly test the role of epigenetics in intestial homeostasis by defining the function of IEC-intrinsic HDAC3. Employing two newly developed mutant mouse strains and established murine models of intestinal inflammation, two specific aims of this project will determine (i) the influence of IEC-intrinsic HDAC3 expression on IEC homeostasis and mucosal barrier function and (ii) how IEC-intrinsic HDAC3 regulates the development and progression of intestinal inflammation and repair. Delineating the contribution of HDAC3 to IEC homeostasis and intestinal disease will significantly expand our understanding of the molecular mechanisms involved in IBD and could impact and justify the development of more selective HDAC inhibitors as therapeutics. During my training as a veterinary pathologist, I discovered my strong interest in epithelial regeneration, mucosal immunology and the pathogenesis of chronic intestinal inflammation. For this reason, I initiated the proposed project with Dr. David Artis that will build upon my knowledge of epigenetics and transcriptional regulation and enable me to transition into the field of mucosal immunology. My thesis work provided me with an excellent foundation in epigenetic regulation, but I have not had previous exposure to immunological techniques and intestinal disease models. The Artis lab and Penn offer an exceptional scientific and intellectual environment that will enable me to utilize modern, innovative approaches in my research and collaborate with top investigators. My understanding of disease pathology in a broad range of species, coupled with my experience in molecular biology and mouse model design and analysis, have provided me with a strong and unique foundation. Over the next five years, I fully anticipate this background in conjunction with my current research plan will allow me to successfully carry out the proposed project. The mentoring and training I will receive in Dr. Artis' laboratory and from the wider Penn community will enable me to successfully transition into an independent veterinary scientist that can address questions directed towards molecular advances in diagnostics as well as innovative and targeted therapeutics for intestinal diseases including IBD and cancer. PUBLIC HEALTH RELEVANCE: Inflammatory bowel diseases (IBD) are complex disorders that represent a significant public health challenge. The goals of this proposal are to understand the influence of a molecule called HDAC3 in the development and function of intestinal cells. Delineating the influence of this molecule on the intestine will expand our understanding of the mechanisms that promote IBD and could impact the development of more effective drugs to treat IBD.