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.

描述（由申请人提供）：候选人：我的研究背景和经验为医师科学家的职业提供了基础。我在内分泌学和基础科学背景和免疫学研究生培训方面的临床培训使我有一个独特的机会将研究重点放在免疫学，内分泌学和代谢的交集上。我对蛋白质激素如何影响免疫感特别感兴趣。在接下来的五年中，我的目标是获得作为独立调查员职业所必需的持续指导和培训。在此期间，我将在Jeffrey Rathmell博士的实验室中获得额外的指导和培训，在那里我将开发淋巴细胞生物学，代谢和转基因小鼠技术的新技能。小儿内分泌部门负责人迈克尔·弗洛克（Michael Freemark）博士将担任我的学术导师和研究顾问。我接下来五年的目标包括：（1）提高我在淋巴细胞生物学，代谢和使用小动物模型领域的科学能力和技能； （2）发表高质量的，同行评审的科学期刊，并在国家会议上介绍我的数据； （3）获得过渡到独立性所必需的经验和科学知识； （4）在五年授予期结束之前，准备成功申请独立调查员奖。 环境：杜克大学医学中心的儿科系致力于培训学术医师科学家进行研究，以促进儿童的健康和福祉，因此为初级调查员提供了丰富的资源环境。这些资源包括指导委员会，教师发展办公室，大学系之间的公开合作以及最先进的实验室和动物住房设施。在Stedman营养和代谢中心以及与其他部门其他教职员工的每周研讨会中的其他成员资格将提供智力刺激，以促进批判性思维和科学讨论。 研究：营养剥夺通过降低细胞介导的和体液免疫，吞噬细胞功能，补体激活和细胞因子的产生来损害免疫功能。在营养不良中看到的脂肪组织缺陷会导致脂肪激素瘦素的缺乏，这在代谢调节以及免疫功能的发展中起着关键作用。缺乏瘦素的个体在总T和CD4 T细胞数量以及异常T细胞功能的情况下都有降低，使其更容易受到细胞内感染和特应性疾病的影响，而重组瘦素蛋白的给药会反转代谢缺陷和免疫异常。瘦素调节淋巴细胞数和功能的机制尚不完全了解。初步数据表明，瘦素对T细胞功能的影响需要通过在T细胞受体（TCR）和共刺激膜蛋白CD28处发出信号来激活T细胞。瘦素激活淋巴细胞中代谢介质AMP激活的蛋白激酶（AMPK）。该瘦素对于活化细胞中的葡萄糖摄取是必需的。由于这些原因，我们假设瘦素对淋巴细胞数和功能的影响需要全T细胞刺激，并且部分是由瘦素对细胞代谢的影响所介导的。为了检验这一假设，我们提出了以下特定目的：（1）我们将确定允许T细胞对瘦素敏感所需的信号； （2）我们将测试以下假设：瘦素通过激活葡萄糖摄取和代谢增加细胞能量，并且AMPK激活是T细胞中瘦素刺激后葡萄糖代谢的重要介体。 （3）我们将检验以下假设：瘦素信号对于体内最佳外周T细胞功能和代谢很重要。这些研究的结果应提供有关瘦素调节淋巴细胞数量和功能的机制的新见解，并可能为营养疾病中免疫功能障碍的发病机理和治疗提供新的方法。