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，代表着重大的公共卫生挑战。了解IBD发病的细胞和分子机制对于识别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提供了一种基本的屏障，在调节肠道微环境中的免疫细胞方面起着至关重要的作用，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认组蛋白脱乙酰酶(HDAC)抑制剂是治疗肠道炎症的假定疗法，但HDAC在肠道健康和疾病中的意义仍不清楚。这项提案中概述的研究将通过定义IEC固有的HDAC3的功能，直接测试表观遗传学在肠内稳态中的作用。利用两个新开发的突变小鼠品系和建立的小鼠肠道炎症模型，该项目的两个具体目标将确定(I)IEC固有的HDAC3表达对IEC动态平衡和粘膜屏障功能的影响以及(Ii)IEC固有的HDAC3如何调节肠道炎症和修复的发展和进展。阐明HDAC3对IEC动态平衡和肠道疾病的贡献将极大地扩展我们对IBD分子机制的理解，并可能影响和证明开发更具选择性的HDAC抑制剂作为治疗药物的合理性。在我作为一名兽医病理学家的培训期间，我发现我对上皮再生、粘膜免疫学和慢性肠炎的发病机制有着浓厚的兴趣。出于这个原因，我与David Artis博士一起发起了这个拟议的项目，该项目将建立在我对表观遗传学和转录调控的知识的基础上，并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表观遗传调控的良好基础，但我以前没有接触过免疫学技术和肠道疾病模型。阿尔蒂斯实验室和宾夕法尼亚大学提供了一个特殊的科学和智力环境，使我能够利用现代的， 在我的研究中采用创新的方法，并与顶级调查人员合作。我对广泛物种的疾病病理学的理解，再加上我在分子生物学和老鼠模型设计和分析方面的经验，为我提供了一个强大而独特的基础。在接下来的五年里，我完全期待这一背景与我目前的研究计划相结合，使我能够成功地实施拟议的项目。我将在Artis博士的实验室和更广泛的宾夕法尼亚社区接受的指导和培训将使我能够成功地转变为一名独立的兽医科学家，能够解决与诊断方面的分子进步有关的问题，以及针对肠道疾病(包括IBD和癌症)的创新和有针对性的疗法。 公共卫生相关性：炎症性肠病(IBD)是一种复杂的疾病，代表着重大的公共卫生挑战。这项提议的目标是了解一种名为HDAC3的分子在肠道细胞发育和功能中的影响。阐明这种分子对肠道的影响将扩大我们对促进IBD的机制的理解，并可能影响治疗IBD的更有效药物的开发。

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.