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。作为外科医生治疗的许多疾病过程的发病机制的主要促成因素，超重和肥胖对当今的外科实践具有深远的影响。我们研究的广泛、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中的关键作用，我们通过检查参与能量稳态的下丘脑基因来研究超重和肥胖。在这个竞争性的更新中，我们概述了一个继续这一研究途径的计划。我们建议继续研究下丘脑黑皮质素能系统，这是一个重要的能量稳态系统，由黑皮质素受体（MCR）亚型MC 3R和MC 4 R，对立的神经肽α黑素细胞刺激激素（α-MSH）和刺豚鼠相关蛋白（AgRP）和syndecan-3组成。我们还建议继续分析伴随能量不平衡状态的下丘脑基因表达变化。为了继续进行在最初的RO 1中启动的研究，该提案有四个具体目标。具体目标1是鉴定MC 4 R配体结合口袋。这将涉及MC 4 R和受体诱变的三维计算机建模。具体目标2是鉴定AgRP的功能区域。这将涉及修饰的AgRP蛋白的合成。具体目标1和2的目的是在分子水平上检查黑皮质素能系统组分之间发生的相互作用。具体目标3是确定在食物剥夺大鼠和肥胖Ay小鼠（一种黑素皮质素能系统缺陷的小鼠）中差异表达的下丘脑基因。这将涉及差异基因表达技术的使用。具体目标4是研究米诺地尔磺基转移酶，血清糖皮质激素诱导激酶，和EST AA 818585，我们的微阵列研究确定的基因，在能量稳态的作用。这将涉及使用神经解剖技术和体内生理实验。具体目标3和4的目的是扩大对能量稳态复杂过程的理解。

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.