Leptin as a Regulator of T Cell Metabolism and Function

瘦素作为 T 细胞代谢和功能的调节剂

• 批准号: 8448733
• 负责人: Nancie MacIver
• 金额: $ 13.62万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-19 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448733
• 关键词: 5' -AMP-activated protein kinase; Academic Medical Centers; Academic Training; Adipocytes; Adipose tissue; Affect; Animal Housing; Animal Model; Antioxidants; Area; Award; Basic Science; Body Weight; CD28 gene; CD4 Positive T Lymphocytes; Cell Count; Cell Proliferation; Cell physiology; Cells; Cessation of life; Child; Childhood; Clinical; Collaborations; Complement Activation; Cytokine Activation; Data; Defect; Deposition; Development; Disease; Eating; Endocrine; Endocrinology; Energy Metabolism; Environment; Experimental Models; Faculty; Fatty Acids; Fatty acid glycerol esters; Glucose Transporter; Glycolysis; Goals; Grant; Health; Hormones; Human; Humoral Immunities; Hypothalamic structure; Immune; Immune System Diseases; Immunity; Immunologics; Immunology; In Vitro; Individual; Infection; Journals; Knowledge; Laboratories; Laboratory Animals; Lead; Leptin; Leptin deficiency; Link; Lymphocyte; Lymphocyte Biology; Lymphocyte Count; Lymphocyte Function; Macronutrients Nutrition; Malnutrition; Mediating; Mediator of activation protein; Membrane; Membrane Proteins; Mentors; Metabolic; Metabolic Activation; Metabolic Pathway; Metabolism; Minerals; Mus; Muscle Cells; Nutrition Disorders; Nutritional; Nutritional status; Organism; Pathogenesis; Peer Review; Peripheral; Personal Satisfaction; Phagocytes; Phosphorylation; Phosphotransferases; Physicians; Play; Predisposition; Production; Proteins; Publishing; RNA Interference; Recombinants; Recurrence; Regulation; Research; Research Personnel; Resources; Risk; Role; Scientist; Signal Transduction; Starvation; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Th1 Cells; Thinking; Time; Tissues; Training; Transgenic Mice; Universities; career; cell growth; cofactor; cytokine; deprivation; experience; glucose metabolism; glucose uptake; immune function; in vivo; insight; interest; leptin receptor; meetings; micronutrient deficiency; novel; novel strategies; nutrition; oxidation; pediatric department; protein kinase P; public health relevance; receptor; skills; uptake; wasting

DESCRIPTION (provided by applicant): CANDIDATE: My research background and experiences have provided the groundwork for a career as a physician scientist. My clinical training in endocrinology and my basic science background and graduate training in immunology give me the unique opportunity to focus my research in the intersection of immunology, endocrinology, and metabolism. I am particularly interested in how protein hormones affect immunity. My goal over the next five years is to receive the ongoing mentoring and training necessary for a career as an independent investigator. During this time I will receive additional mentoring and training in Dr. Jeffrey Rathmell's laboratory, where I will develop new skills in lymphocyte biology, metabolism, and transgenic mouse technology. Dr. Michael Freemark, Chief of the Pediatric Endocrine division, will serve as my academic mentor and research consultant. My objectives for the next five years include the following: (1) advance my scientific abilities and skills in the areas of lymphocyte biology, metabolism, and the use of small animal models; (2) publish in high-quality, peer-reviewed scientific journals and present my data at national meetings; (3) obtain the experience and scientific knowledge necessary to transition towards independence; and (4) prepare a successful application for an independent investigator award before the end of the five year granting period. ENVIRONMENT: The Department of Pediatrics at Duke University Medical Center is dedicated to training academic physician-scientists to conduct research that will promote the health and well-being of children, and therefore offers an environment rich in resources for the junior investigator. These resources include a mentoring committee, an Office for Faculty Development, open collaboration between University departments, and state-of-the-art laboratories and animal housing facilities. Additional membership in the Stedman Nutrition and Metabolism Center and weekly seminars with other faculty across several departments will provide intellectual stimulation to promote critical thinking and scientific discussion. RESEARCH: Nutritional deprivation compromises immune function by decreasing cell-mediated and humoral immunity, phagocyte function, complement activation, and cytokine production. Deficits in adipose tissue, as seen in malnutrition, lead to a deficiency of the adipose hormone leptin, which plays a critical role in metabolic regulation as well as the development of immune function. Leptin-deficient individuals have a decrease in both total T and CD4 T cell number along with abnormal T cell function, making them more susceptible to intracellular infections and atopic disease, while administration of recombinant leptin protein reverses both the metabolic defects and immune abnormalities. The mechanisms by which leptin regulates lymphocyte number and function are not completely understood. Preliminary data suggest that leptin's effects on T cell function require activation of the T cell by signaling at both the T cell receptor (TCR) and co-stimulatory membrane protein CD28; that leptin activates the metabolic mediator AMP-activated protein kinase (AMPK) in lymphocytes; and that leptin is necessary for glucose uptake in activated cells. For these reasons, we hypothesize that the effects of leptin on lymphocyte number and function require full T cell stimulation and are mediated in part by leptin's effects on cellular metabolism. To test this hypothesis, we propose the following specific aims: (1) We will identify the signals required to allow T cells to become sensitive to leptin; (2) we will test the hypothesis that leptin increases cellular energy by activating glucose uptake and metabolism, and that AMPK activation is an important mediator of glucose metabolism following leptin stimulation in T cells; and (3) we will test the hypothesis that leptin signal is important for optimal peripheral T cell function and metabolism in vivo. The results of these studies should provide new insight into the mechanisms by which leptin regulates lymphocyte number and function, and may yield new approaches to the pathogenesis and treatment of immune dysfunction in nutritional disorders.

候选人：我的研究背景和经验为成为一名内科科学家提供了基础。我在内分泌学方面的临床训练以及我在免疫学方面的基础科学背景和研究生培训给了我一个独特的机会，把我的研究重点放在免疫学、内分泌学和代谢的交叉领域。我对蛋白质激素如何影响免疫力特别感兴趣。在接下来的五年里，我的目标是接受作为独立调查员的职业生涯所必需的持续指导和培训。在此期间，我将在Jeffrey Rathmell博士的实验室接受额外的指导和培训，在那里我将学习淋巴细胞生物学、新陈代谢和转基因小鼠技术方面的新技能。儿科内分泌科主任Michael Freemark博士将担任我的学术导师和研究顾问。我未来五年的目标包括以下几点：(1)提高我在淋巴细胞生物学、代谢和小动物模型使用方面的科学能力和技能；(2)在高质量、同行评议的科学期刊上发表文章，并在全国性会议上展示我的数据；(3)获得向独立过渡所需的经验和科学知识；(4)在5年授予期结束前准备一份成功的独立研究者奖励申请。