Identification of pathways involved in orbital adipogenesis using functional genomics

“利用功能基因组学鉴定眼眶脂肪形成的途径” 项目摘要/摘要 Graves病，最常见的眼眶炎症性疾病，导致显著 毁容，生活质量下降，以及包括失明在内的眼部疾病。尽管 Graves病的病理生理学还不完全清楚，人们认为是一种免疫 对甲状腺细胞和眼眶成纤维细胞上表达的自身抗原的反应 刺激素受体和胰岛素样生长因子-1受体诱导一系列 炎性细胞因子级联反应，通过纤维化和眼眶软组织扩张 脂肪生成1-8目前的治疗方法侧重于症状控制、抗炎 药物治疗和患者的外科康复，不针对潜在疾病 机械装置。目前，开发和测试针对细胞因子的药物的研究正在进行中 或自身抗原来钝化免疫反应。然而，很少有研究致力于 了解眼眶脂肪形成的机制，眼眶脂肪形成的最终共同途径之一 炎症级联导致眼眶软组织扩张。这一点尤其重要，因为 眼眶成脂作用可能不同于体内其他脂肪组织储存库，其基础是 眼眶脂肪的不同胚胎学来源。 我提出了一个计划，作为一名临床医生-科学家，进行多年的培训，以确定 参与Graves病眼眶脂肪形成的分子途径可能是 潜在的治疗靶点。具体地说，我将重点介绍非编码RNA(NcRNAs)，它 已被证明在多个系统中调节分化，并具有组织特异性 在小鼠不同脂肪库中的表达和功能。10了解基础 NcRNA在眼眶脂肪形成中的作用可能提供潜在的治疗靶点。我会工作的 在高级调查人员的指导下，他们的不同专业领域将在 我的训练。将与我一起工作的导师团队是由NIH资助的富有成效的科学家 对各自领域做出了宝贵贡献的人。我将在……的实验室接受培训 Seth Blackshaw博士，高通量生物学中心主任，学习 功能基因组学，他已将其应用于研究下丘脑和 视网膜。由新陈代谢与肥胖中心的William Wong博士指导 研究，谁在脂肪细胞生物学方面有专长，我将应用在 布莱克肖实验室对眼眶脂肪生成的研究。特里·史密斯博士 密歇根大学的医学和眼科学，炎症信号方面的专家 Graves病的眼眶成纤维细胞，将作为我的导师，将我的教育集中在 细胞因子信号转导与Graves病的脂肪生成。使用这些产品的综合专业知识 导师们，我将学习如何设计实验，以识别功能 在Graves病眼眶脂肪形成中的意义，这两者都使我能够 成为一名独立的研究人员，并获得将导致药物治疗目标的数据。 在我当教员的第一年，我的学术时间都花在了布莱克肖博士的实验室里 筛选小鼠眼眶、棕色、皮下和内脏脂肪组织储存库 确定感兴趣的转录本与眼眶脂肪中的组织特异性表达，这可能有助于阐明 不同脂肪库之间的功能和代谢差异。这项前期工作将 开始我在高通量基因组学和脂肪细胞生物学方面的培训。 我的目标是发展成为一名临床医生兼科学家，负责治疗眼周炎患者和 眼眶疾病，并有一个积极的实验室研究眼眶脂肪生成，目标是 确定ncRNAs为Graves病和其他眼眶疾病的新药物治疗靶点 炎症性疾病。为了实现这个目标，我设计了一个多年的培训计划 在ncRNAs、功能基因组学、脂肪细胞生物学和Graves专家的指导下 疾病。

“Identification of pathways involved in orbital adipogenesis using functional genomics” Project Summary/Abstract Graves disease, the most common orbital inflammatory disease, causes significant disfigurement, decreased quality of life, and ocular morbidity, including blindness. Although the pathophysiology of Graves disease is not entirely understood, it is thought that an immune response to auto-antigens expressed on thyrocytes and orbital fibroblasts, the thyroid stimulating hormone receptor and the insulin-like growth factor-1 receptor, induce a series of inflammatory cytokine cascades that result in orbital soft tissue expansion through fibrosis and adipogenesis.1-8 Current treatment approaches focus on symptom control, anti-inflammatory medications, and surgical rehabilitation of patients, and do not target underlying disease mechanisms. Currently, research is underway to develop and test agents that target cytokines or auto-antigens to blunt the immune response.9 However, little research has been devoted to understand the mechanisms of orbital adipogenesis, one of the final common pathways of the inflammatory cascades causing orbital soft tissue expansion. This is especially important as orbital adipogenesis likely differs from other adipose tissue depots in the body based on the alternate embryologic origins of orbital fat. I propose a plan for multiple years of training as a clinician-scientist working to identify the molecular pathways involved in orbital adipogenesis in Graves disease that may serve as potential therapeutic targets. Specifically, I will focus on non-coding RNAs (ncRNAs), which have been shown to regulate differentiation in multiple systems and have tissue-specific expression and function in different adipose depots in mice.10 Understanding the basis of ncRNA function in orbital adipogenesis may provide potential therapeutic targets. I will work under the mentorship of senior investigators whose diverse areas of expertise will be critical in my training. The team of mentors who will work with me are productive NIH-funded scientists who have made valuable contributions to their respective fields. I will train in the laboratory of Dr. Seth Blackshaw, Director of the Center for High Throughput Biology, learning techniques of functional genomics that he has applied to the study of neurogenesis in the hypothalamus and retina. With the guidance of Dr. William Wong of the Center for Metabolism and Obesity Research, who has expertise in adipocyte biology, I will apply the techniques used in the Blackshaw lab to the study of orbital adipogenesis. Dr. Terry Smith of the Departments of Medicine and Ophthalmology at University of Michigan, an expert in inflammatory signaling in orbital fibroblasts in Graves disease, will serve as a mentor by focusing my education on cytokine signaling and adipogenesis to Graves disease. Using the combined expertise of these mentors, I will learn how to design experiments that will identify transcripts of functional significance during orbital adipogenesis in Graves disease, which both enable me to develop into an independent researcher and acquire the data that will lead to targets for medical therapy. During my first year as faculty, my academic time is being spent in Dr. Blackshaw's lab screening murine orbital, brown, subcutaneous, and visceral adipose tissue depots in order to identify transcripts of interest with tissue specific expression in orbital fat, which may elucidate functional and metabolic differences between the diverse fat depots. This preliminary work will initiate my training in high-throughput genomics and adipocyte biology. My goal is to develop into a clinician-scientist who takes care of patients with periocular and orbital disease and has an active laboratory investigating orbital adipogenesis, with the goal of identifying ncRNAs as targets of novel medical therapies for Graves disease and other orbital imflammatory diseases. In order to achieve this goal, I have designed a multi-year training plan under the mentorship of experts in ncRNAs, functional genomics, adipocyte biology, and Graves disease.