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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生成的途径

基本信息

批准号：
10004056
负责人：
Fatemeh Rajaii
金额：
$ 17.24万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004056
关键词：
Abdomen Adipose tissue Anti-Inflammatory Agents Area Attention Biochemical Bioinformatics Biology Blindness CRISPR interference Cell Survival Cells Cellular Assay Collaborations Core Facility Cytokine Signaling Data Development Disease Education Faculty Fatty acid glycerol esters Fibroblasts Fibrosis Functional disorder Funding Genes Genomics Goals Graves&apos Disease Human Hypothalamic structure Immune response In Vitro Inflammatory Institutional Review Boards Insulin-Like-Growth Factor I Receptor Knockout Mice Laboratories Learning Medical Medicine Mentors Mentorship Mesenchyme Metabolic Metabolism Methods Michigan Molecular Morbidity - disease rate Mus Neural Crest Obesity Ocular orbit Operative Surgical Procedures Ophthalmology Orbital Diseases Pathway interactions Patient Care Patients Pharmaceutical Preparations Pharmacotherapy Protein Microchips Protocols documentation Quality of life RNA RNA Interference Rehabilitation therapy Research Research Personnel Retina Reverse Transcriptase Polymerase Chain Reaction Scientist Series Signal Transduction Surgeon Symptoms System Techniques Testing Thyrotropin Receptor Time Tissue Expansion Tissues To autoantigen Training Transcript United States National Institutes of Health Universities Untranslated RNA Visceral Visceral fat Work abdominal fat adipocyte biology adipocyte differentiation base cDNA Library cytokine deep sequencing design differential expression disorder control experimental study expression vector functional genomics gain of function gene function human tissue in vivo interest lipid biosynthesis loss of function neurogenesis novel progenitor screening soft tissue subcutaneous targeted agent targeted treatment therapeutic target therapy development transcriptome transcriptome sequencing

项目摘要

“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.

利用功能基因组学鉴定眼眶脂肪形成的途径