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

基本信息

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
项目类别：
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&apos -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

项目摘要

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.

描述（由申请人提供）：候选人：我的研究背景和经验为我作为一名医师科学家的职业生涯奠定了基础。我在内分泌学方面的临床培训、基础科学背景以及免疫学方面的研究生培训为我提供了独特的机会，使我能够将研究重点放在免疫学、内分泌学和新陈代谢的交叉领域。我对蛋白质激素如何影响免疫力特别感兴趣。我未来五年的目标是接受独立调查员职业所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，在那里我将发展淋巴细胞生物学、新陈代谢和转基因小鼠技术方面的新技能。儿科内分泌科主任迈克尔·弗里马克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：（1）提高我在淋巴细胞生物学、新陈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、经过同行评审的科学期刊上发表文章，并在全国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) 在五年授予期结束之前准备成功的独立研究者奖申请。环境：杜克大学医学中心儿科致力于培训学术医师科学家开展促进儿童健康和福祉的研究，因此为初级研究人员提供了资源丰富的环境。这些资源包括指导委员会、教师发展办公室、大学各院系之间的开放合作以及最先进的实验室和动物饲养设施。斯特德曼营养和代谢中心的额外会员资格以及与多个系的其他教员每周举行的研讨会将提供智力刺激，以促进批判性思维和科学讨论。研究：营养缺乏会降低细胞介导的体液免疫、吞噬细胞功能、补体激活和细胞因子的产生，从而损害免疫功能。脂肪组织的缺陷，如营养不良，会导致脂肪激素瘦素的缺乏，而瘦素在代谢调节和免疫功能的发展中起着至关重要的作用。瘦素缺陷个体的 T 细胞总数和 CD4 T 细胞数量均减少，T 细胞功能异常，使他们更容易受到细胞内感染和特应性疾病的影响，而重组瘦素蛋白的施用可以逆转代谢缺陷和免疫异常。瘦素调节淋巴细胞数量和功能的机制尚不完全清楚。初步数据表明，瘦素对 T 细胞功能的影响需要通过 T 细胞受体 (TCR) 和共刺激膜蛋白 CD28 的信号传导来激活 T 细胞。瘦素激活淋巴细胞中的代谢介质 AMP 激活蛋白激酶 (AMPK)；瘦素是活化细胞摄取葡萄糖所必需的。由于这些原因，我们假设瘦素对淋巴细胞数量和功能的影响需要充分的 T 细胞刺激，并且部分是由瘦素对细胞代谢的影响介导的。为了检验这一假设，我们提出以下具体目标：（1）我们将识别T细胞对瘦素敏感所需的信号； (2) 我们将检验瘦素通过激活葡萄糖摄取和代谢来增加细胞能量的假设，以及 AMPK 激活是瘦素刺激 T 细胞后葡萄糖代谢的重要介质； (3) 我们将检验瘦素信号对于最佳外周 T 细胞功能和体内代谢很重要的假设。这些研究的结果应该为瘦素调节淋巴细胞数量和功能的机制提供新的见解，并可能为营养性疾病中免疫功能障碍的发病机制和治疗提供新的方法。