Neuroendocrinology of energy balance control: role of glucagon-like-peptide-1

描述（由申请人提供）： 项目概要：候选人、环境和研究。该提案描述了一个为期5年的培训计划，旨在为候选人提供实现其长期目标所需的专业知识，即在一所学术研究型大学发展独立的行为神经科学家职业生涯。候选人获得了博士学位。2006年，他在宾夕法尼亚大学心理学系和神经科学研究生组担任博士后研究员。心理学和神经科学研究生团体都有完善的研究计划和强大的研究传统，与宾夕法尼亚大学的其他跨学科研究所一起，将为候选人提供理想的培训环境。Harvey J. Grill博士是行为神经科学领域的知名研究人员，也是控制食物摄入和能量消耗的神经回路和神经化学系统的专家。鉴于拟议研究的新颖跨学科方法，候选人还将由共同导师Kendra K.他是糖尿病和肥胖症研究领域的一位杰出的初级分子生物学家。该研究计划的重点是神经肽胰高血糖素样肽-1（GLP-1）及其在控制食物摄入、体重调节和葡萄糖稳态方面的作用。本文所述的实验利用新的体内和体外方法来确定：[1]迷走神经传入纤维上GLP-1受体对血糖和能量平衡调节的必要性; [2]食物摄入抑制和对后脑背侧孤束核中后脑GLP-1受体表达神经元的外源性和内源性激活的血糖反应;[3]通过激活后脑GLP-1受体介导抑制摄入的细胞内信号传导途径。了解调节GLP-1受体激活的能量平衡和血糖效应的生理机制、受体群体和细胞内信号传导途径，有可能为旨在预防和治疗肥胖症和II型糖尿病的药物开发提供新的见解。 公共卫生相关性： 基础科学发现已经确定了特定的大脑化学系统，可以在受到刺激时减少食物摄入。这些发现正在推动旨在预防或治疗肥胖的药物开发;然而，迄今为止，还没有有效的药物治疗肥胖。这里采用了一种新的方法;我们认为，如果基础研究专注于了解激素胰高血糖素样肽-1的天然生理机制，受体群体和信号通路，可以取得更多进展，为未探索的肥胖药物治疗方案提供见解。

DESCRIPTION (provided by applicant): Project summary: candidate, environment, and research. This proposal describes a 5-year training program designed to provide the candidate with the expertise needed to achieve his long-term goal of developing a career as an independent behavioral neuroscientist at an academic research university. The candidate received a Ph.D. in 2006 and has since been conducting research as a postdoctoral fellow in the Department of Psychology and the Neuroscience Graduate Groups at the University of Pennsylvania. Both the Psychology and Neuroscience Graduate Groups have well-established research programs and a strong research tradition that together with other interdisciplinary institutes at the University of Pennsylvania will provide an ideal training environment for the candidate. The proposed primary mentor, Dr. Harvey J. Grill is a well-established researcher in the field of behavioral neuroscience and an expert in the neural circuits and neurochemical systems that control food intake and energy expenditure. Given the novel interdisciplinary approaches of the proposed research the candidate will also be guided by a co-mentor, Dr. Kendra K. Bence, a prominent junior molecular biologist in the fields of diabetes and obesity research. The research plan focuses on the neuropeptide glucagon-like-peptide-1 (GLP-1) and its role in controlling for food intake, body weight regulation and glucose homeostasis. The experiments described here take advantage of novel in vivo and in vitro approaches to determine: [1] the necessity of GLP-1 receptors on vagal afferent fibers to glycemic and energy balance regulation; [2] the food intake inhibition and glycemic responses to exogenous and endogenous activation of hindbrain GLP-1 receptor-expressing neurons in the nucleus tractus solitarius of the dorsal hindbrain; [3] the intracellular signaling pathways mediating the suppression of intake by hindbrain GLP-1 receptor activation. Understanding the physiological mechanisms, receptor populations and intracellular signaling pathways mediating the energy balance and glycemic effects of GLP-1 receptor activation has the potential to reveal novel insights for pharmaceutical drug developments aimed at preventing and treating obesity and Type II Diabetes Mellitus. PUBLIC HEALTH RELEVANCE: Basic science discoveries have identified specific brain chemical systems that can reduce food intake when stimulated. These discoveries are driving pharmaceutical developments aimed at preventing or treating obesity; however, to date, there are no effective drug treatments for obesity. A novel approach is taken here; we think that more progress could be made if basic research were to focus on understanding the natural physiological mechanisms, receptor populations, and signaling pathways of the hormone glucagon-like-peptide-1, providing insights into unexplored obesity drug treatment options.