Regulation of adipose inflammation and metabolic syndrome by adipsin/factor D

描述（由申请人提供）：本研究计划概述了詹姆斯C。罗医生哲学博士、布里格姆妇女医院和哈佛医学院的心脏病学研究员，在布鲁斯斯皮格尔曼博士的指导下，丹娜法伯癌症研究所和哈佛医学院细胞生物学和医学教授。Spiegelman博士是美国国家科学院院士，也是脂肪生物学和代谢疾病方面的世界级专家。重要的是，Spiegelman博士在指导科学家方面有着良好的记录，有20多名学员担任学术教师职位。咨询委员会由G khan Hotamisligil，M. D，Ph.D.哈佛公共卫生学院教授，Diane马西斯博士。哈佛医学院教授，医学博士埃文罗森，博士贝丝以色列女执事医疗中心的副教授将提供能量稳态，炎症，压力，脂质代谢，脂肪细胞谱系承诺/分化和免疫调节方面的专业知识。Lo博士将利用Spiegelman实验室和周围哈佛医学院校园的世界级环境，包括Dana-Farber癌症研究所和Brigham and Women's医院，以实现提案中的目标。该计划允许Lo博士在代谢和炎症疾病的交叉点发展专业知识，并过渡到独立研究者。肥胖是心血管疾病的独立危险因素。最近的研究强调了脂肪组织炎症和代谢疾病之间的密切联系。脂肪炎症驱动代谢综合征的发展。脂肪蛋白酶/补体因子D是多种肥胖模型中缺乏的脂肪特异性免疫因子。脂蛋白酶控制的速率限制步骤的替代 补体途径，并产生过敏毒素C3a，一种有效的免疫激活剂。这使得adipsin成为协调脂肪组织炎症以及随后的肥胖和炎症的代谢后果的主要候选者。本项目的主要目的是确定adipsin在肥胖和糖尿病发病机制中的作用，并测试adipsin导向治疗是否可以有效治疗代谢性疾病。研究人员将采用adipsin缺陷小鼠进行体内代谢研究，在adipsin途径中重组蛋白以剖析机制，并测试用于治疗肥胖和糖尿病的新型adipsin导向疗法。

DESCRIPTION (provided by applicant): This research proposal outlines a 5-year career development plan for James C. Lo, M.D., Ph.D., cardiology fellow at Brigham and Women's Hospital and Harvard Medical School to achieve independence as a principal investigator under the mentorship of Bruce Spiegelman, Ph.D., Professor of Cell Biology and Medicine at the Dana-Farber Cancer and Harvard Medical School. Dr. Spiegelman is a member of the National Academy of Sciences and a world expert on adipose biology and metabolic diseases. Importantly, Dr. Spiegelman has a strong track record of mentoring scientists with over 20 trainees holding academic faculty positions. An advisory committee composed of G¿khan Hotamisligil, M.D, Ph.D. Professor at the Harvard School of Public Health, Diane Mathis, Ph.D. Professor at Harvard Medical School, and Evan Rosen, M.D., Ph.D. Associate Professor at Beth Israel Deaconess Medical Center will provide expertise on energy homeostasis, inflammation, stress, lipid metabolism, adipocyte lineage commitment/differentiation, and immune regulation. Dr. Lo will take advantage of the world class environment at the Spiegelman lab and surrounding Harvard Medical School campus, including the Dana-Farber Cancer Institute and Brigham and Women's Hospital to achieve the aims in the proposal. This plan allows Dr. Lo to develop expertise at the intersection of metabolic and inflammatory diseases and transition to an independent investigator. Obesity is an independent risk factor for cardiovascular disease. Recent studies have highlighted the intimate link between adipose tissue inflammation and metabolic diseases. Adipose inflammation drives the development of metabolic syndrome. Adipsin/complement factor D is an adipose-specific immune factor deficient in multiple models of obesity. Adipsin controls the rate-limiting step in the alternative complement pathway and generates the anaphylatoxin C3a, a potent immune activator. This places adipsin as a prime candidate to coordinate adipose tissue inflammation and the ensuing metabolic consequences of obesity and inflammation. The major objective of this project is to determine the function of adipsin in the pathogenesis of obesity and diabetes and to test whether adipsin-directed therapy can be an effective treatment for metabolic disease. The investigator will employ adipsin-deficient mice for in vivo metabolic studies, recombinant proteins within the adipsin pathway to dissect the mechanism, and test novel adipsin-directed therapies for treatment of obesity and diabetes.