?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.
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