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

描述(由申请人提供)： 项目总结：候选人、环境和研究。这份提案描述了一项为期5年的培训计划，旨在为应聘者提供所需的专业知识，以实现他作为一所学术研究大学的独立行为神经学家的职业生涯的长期目标。这位候选人于2006年获得博士学位，此后一直在宾夕法尼亚大学心理学系和神经科学研究生组从事博士后研究。心理学和神经科学研究生组都有完善的研究项目和强大的研究传统，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。被提名的首席导师哈维·J·格里尔博士是行为神经科学领域的知名研究人员，也是控制食物摄入量和能量消耗的神经回路和神经化学系统方面的专家。考虑到拟议研究的新的跨学科方法，候选人还将由共同导师肯德拉·K·本斯博士指导，肯德拉·K·本斯博士是糖尿病和肥胖症研究领域的著名初级分子生物学家。该研究计划的重点是神经肽类胰高血糖素-1(GLP-1)及其在控制食物摄入量、体重调节和血糖稳态方面的作用。本文描述的实验利用体内和体外的新方法来确定：[1]迷走神经传入纤维上的GLP-1受体对血糖和能量平衡调节的必要性；[2)后脑孤束核中表达GLP-1受体的神经元对外源性和内源性激活的摄食抑制和血糖反应；[3)通过激活后脑GLP-1受体介导摄食抑制的细胞内信号通路。了解GLP-1受体激活调节能量平衡和升糖效应的生理机制、受体种群和细胞内信号通路，将有可能为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，这些系统可以在受到刺激时减少食物的摄入量。这些发现正在推动旨在预防或治疗肥胖症的药物开发；然而，到目前为止，还没有有效的肥胖症药物治疗方法。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类胰高血糖素肽-1的自然生理机制、受体种群和信号通路，为尚未探索的肥胖症药物治疗方案提供见解，可能会取得更大进展。

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.