Obesity is a Surgical Problem

描述(由申请人提供)： 超重和肥胖是重要的外科问题。作为外科医生治疗许多疾病过程的主要致病因素，超重和肥胖对当今的外科实践有着深远的影响。我们研究的长期目标是研究超重和肥胖的分子基础。由于下丘脑在控制体重方面起着关键作用，我们通过检测下丘脑中与能量平衡有关的基因来研究超重和肥胖。在这次竞争性的更新中，我们概述了一个继续这一研究途径的计划。我们建议继续我们对下丘脑黑素皮质素能系统的研究，这是一个重要的能量平衡系统，包括黑素皮质素受体(MCR)亚型MC3R和MC4R，相反的神经肽α-黑素细胞刺激素(α-MSH)和刺鼠相关蛋白(AgRP)，以及syndecan-3。我们还建议继续分析伴随能量失衡状态的下丘脑基因表达变化。为了继续在最初的RO1中发起的研究，该提案有四个具体目标。具体目的1是鉴定MC4R配体结合口袋。这将涉及对MC4R和受体突变的三维计算机建模。具体目的2是确定AgRP的功能区。这将涉及到修饰的AgRP蛋白质的合成。具体目标1和2的目的是在分子水平上检查发生在黑素皮质能系统各组成部分之间的相互作用。具体目标3是确定在缺乏食物的大鼠和肥胖的Ay小鼠中差异表达的下丘脑基因，Ay小鼠是一种黑素皮质能系统缺陷的小鼠。这将涉及到差异基因表达技术的使用。具体目的4是研究米诺地尔磺基转移酶、血清糖皮质激素诱导的激酶和EST AA818585基因在能量平衡中的作用。这将涉及神经解剖学技术和活体生理实验的使用。具体目标3和4的目的是扩大对能量动态平衡的复杂过程的理解。

DESCRIPTION (provided by applicant): Overweight and obesity are important surgical problems. As major contributing factors to the pathogenesis of many disease processes treated by the surgeon, overweight and obesity have a profound impact on present day surgical practice. The broad, long-term objective of our research has been to study the molecular basis of overweight and obesity. Because of the key role of the hypothalamus in the control of body weight we have approached our study of overweight and obesity by examining hypothalamic genes involved in energy homeostasis. In this competing renewal we outline a plan to continue this avenue of research. We propose to continue our study of the hypothalamic melanocortinergic system, an important energy homeostatic system that consists of the melanocortin receptor (MCR) subtypes MC3R and MC4R, the opposing neuropeptides alpha melanocyte-stimulating hormone (alpha-MSH) and agouti-related protein (AgRP), and syndecan-3. We also propose to continue our analysis of hypothalamic gene expression changes that accompany states of energy imbalance. To continue research that was initiated in the original RO1 this proposal has four specific aims. Specific Aim 1 is to identify MC4R ligand binding pockets. This will involve three-dimensional computer modeling of the MC4R and receptor mutagenesis. Specific Aim 2 is to identify the functional regions of AgRP. This will involve the synthesis of modified AgRP proteins. The intent of Specific Aims 1 and 2 is to examine at a molecular level the interactions that occur between components of the melanocortinergic system. Specific Aim 3 is to identify hypothalamic genes that are differentially expressed in the food-deprived rat and the obese Ay mouse, a mouse that has a defect in the melanocortinergic system. This will involve the use of differential gene expression technologies. Specific Aim 4 is to study the role of minoxidil sulfotransferase, serum glucocorticoid-inducible kinase, and EST AA818585, genes identified by our microarray studies, in energy homeostasis. This will involve the use of neuroanatomical techniques and in vivo physiological experiments. The intent of Specific Aims 3 and 4 is to expand understanding of the complex process of energy homeostasis.