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

Adipsin/D 因子对脂肪炎症和代谢综合征的调节

• 批准号: 8425718
• 负责人: James C Lo
• 金额: $ 15.92万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8425718
• 关键词: Address; Adipocytes; Adipose tissue; Advisory Committees; Alternative Complement Pathway; Anaphylatoxins; Area; Biochemical; Biological Assay; Biology; Blood Vessels; Cardiology; Cardiovascular Diseases; Cells; Cellular biology; Clinical; Complement 3a; Complement Factor D; Dana-Farber Cancer Institute; Data; Developed Countries; Development; Development Plans; Diabetes Mellitus; Diet; Disease; Doctor of Medicine; Doctor of Philosophy; Environment; Faculty; Flow Cytometry; Functional disorder; Gene Expression; Genetic; Genetic Models; Glucose Intolerance; Health; Homeostasis; Hospitals; Immune; Inflammation; Inflammatory; Israel; K-Series Research Career Programs; Knockout Mice; Link; Malignant Neoplasms; Medical center; Medicine; Mentors; Mentorship; Metabolic; Metabolic Diseases; Metabolic syndrome; Modeling; Molecular; Mus; Obesity; Pathogenesis; Pathway interactions; Play; Positioning Attribute; Prevalence; Principal Investigator; Public Health Schools; Recombinant Proteins; Regulation; Research Personnel; Research Proposals; Risk Factors; Role; Scientist; Stress; Testing; Tissues; Transgenic Mice; Transgenic Organisms; United States National Academy of Sciences; Woman; adipsin; blood glucose regulation; career development; chemokine; cytokine; diabetic; effective therapy; improved; in vivo; lipid metabolism; macrophage; medical schools; member; metabolic abnormality assessment; mortality; novel; novel therapeutic intervention; obesity treatment; professor; research study; restoration; tool; trend

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. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the leading cause of mortality in the US and the recent trend of increasing prevalence of obesity and diabetes threaten to exacerbate this health problem. This career development award outlines a multi-step plan to understand the molecular link between metabolic and inflammatory diseases and to establish an independent investigator with expertise in this area. Understanding and being able to manipulate these pathways has the potential for development of novel therapies against obesity and diabetes.

描述（由应用程序提供）：该研究提案概述了詹姆斯·C·罗（James C. Spiegelman博士是美国国家科学院的成员，也是脂肪生物学和代谢疾病的世界专家。重要的是，Spiegelman博士在心理科学家方面拥有良好的记录，拥有20多名学员担任学术教师职位。由M.D. Ghan Hotamisligil博士组成的咨询委员会哈佛大学公共卫生学院教授黛安·马蒂斯（Diane Mathis）博士哈佛医学院教授和医学博士Evan Rosen博士贝丝以色列执事医学中心副教授将提供有关能量稳态，感染，压力，脂质代谢，脂肪细胞谱系承诺/差异化和免疫调节的专业知识。 Lo博士将在Spiegelman实验室和周围的哈佛医学院校园里利用世界一流的环境，包括Dana-Farber癌症研究所以及Brigham and妇女医院，以实现该提案的目标。该计划使LO博士能够在代谢和炎症性疾病的交汇处发展专业知识，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感染与代谢疾病之间的紧密联系。脂肪注射驱动代谢综合征的发展。脂肪蛋白/补体因子D是多种肥胖模型中缺乏脂肪特异性的免疫因子。 adipsin控制替代方案的限速步骤 补体途径并生成潜在的免疫活化剂过敏毒素C3A。这个位置adipsin是协调脂肪组织感染以及确保肥胖和感染的代谢后果的主要候选者。该项目的主要目的是确定脂肪素在肥胖和糖尿病的发病机理中的功能，并测试脂肪素定向的治疗是否可以有效地治疗代谢疾病。研究者将利用脂肪素缺陷小鼠进行体内代谢研究，在脂肪蛋白途径内重组蛋白进行解剖，并测试新型脂肪素指导的疗法以治疗肥胖症和糖尿病。 公共卫生相关性：心血管疾病是美国死亡率的主要原因，肥胖症和糖尿病患病率增加的最新趋势可能会加剧这一健康问题。该职业发展奖概述了一个多步计划，以了解代谢疾病和炎症性疾病之间的分子联系，并与该领域的专家建立独立的研究者。理解和能够操纵这些途径具有开发针对肥胖和糖尿病的新疗法的潜力。