Identification of pathways involved in orbital adipogenesis using functional genomics

“使用功能基因组学鉴定参与眼眶脂肪形成的途径” 项目总结/摘要 Graves病是最常见的眼眶炎性疾病， 毁容、生活质量下降和眼部疾病，包括失明。虽然 Graves病的病理生理学尚未完全了解，人们认为， 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 炎性细胞因子级联通过纤维化导致眼眶软组织扩张， 1 -8目前的治疗方法主要集中在症状控制、抗炎、 药物和患者的手术康复，并且不针对基础疾病 机制等目前，正在研究开发和测试针对细胞因子的药物 或自身抗原来减弱免疫反应。9然而，很少有研究致力于 了解眼眶脂肪形成的机制，这是最后的共同途径之一， 导致眼眶软组织扩张的炎症级联反应。这一点尤其重要，因为 眼眶脂肪形成可能不同于体内其他脂肪组织库， 眶脂肪的交替胚胎起源。 我提出了一个多年的培训计划，作为一名临床科学家， 参与Graves病眼眶脂肪形成的分子途径， 潜在的治疗靶点。具体来说，我将集中在非编码RNA（ncRNA）， 已显示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。 ncRNA在眼眶脂肪形成中的功能可能提供潜在的治疗靶点。我将 在高级调查员的指导下，他们的不同专业领域在以下方面至关重要： 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 他们在各自的领域做出了宝贵的贡献。我将在实验室里训练 博士塞思·布莱克肖，高密度生物学中心主任， 他将功能基因组学应用于下丘脑神经发生的研究， 视网膜。在代谢和肥胖中心的William Wong博士的指导下， 研究，谁在脂肪细胞生物学的专业知识，我将应用所使用的技术， 布莱克肖实验室研究眼眶脂肪形成。特里·史密斯博士， 密歇根大学医学和眼科学教授， 眼眶成纤维细胞在格雷夫斯病，将作为一个导师，通过集中我的教育， 细胞因子信号传导和脂肪生成与Graves病的关系。利用这些专家的综合专长， 导师，我将学习如何设计实验，将确定转录的功能 在Graves病的眼眶脂肪形成过程中的重要性，这两者都使我能够发展 成为一个独立的研究人员，并获得数据，将导致目标的医学治疗。 在我当教员的第一年里，我的学术时间是在布莱克肖博士的实验室里度过的。 筛选小鼠眼眶、棕色、皮下和内脏脂肪组织库， 鉴定在眼眶脂肪中具有组织特异性表达的感兴趣的转录物，这可以阐明 不同脂肪库之间的功能和代谢差异。这项初步工作将 开始我的高通量基因组学和脂肪细胞生物学的训练。 我的目标是发展成为一名临床科学家谁照顾病人的眼周和 眼眶疾病，并有一个活跃的实验室研究眼眶脂肪形成，目标是 鉴定ncRNA作为Graves病和其他眼眶疾病的新药物治疗的靶点 炎症性疾病。为了实现这一目标，我设计了一个多年培养计划 在ncRNA、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.