PROTEOMIC STUDY OF HEPATIC METABOLISM REGULATED BY HYPOTHALAMIC PATHWAYS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 下丘脑中-基底核（MBH）在控制肝脏葡萄糖稳态中起着关键作用。 MBH感测循环营养物如葡萄糖和脂肪酸以及激素如瘦素和胰岛素，从而评估生物体的能量状态。 当餐后状态下营养物质和胰岛素的循环水平升高时，从MBH下降的途径被激活，肝葡萄糖产生（hGP）被抑制。 在胰岛素抵抗（IR）状态下，胰岛素不能抑制肝葡萄糖产生（hGP），这部分是由于MBH对hGP的控制丧失。通过激活这些中枢通路而在外周组织中发生的分子事件知之甚少。 该提案的总体目标是利用来自资源的高灵敏度、高分辨率LC-MS定量蛋白质组学来鉴定由MBH活化诱导的总组织以及亚细胞区室（包括胞质、线粒体和膜组分）中蛋白质水平的差异。我们的目的是确定差异蛋白质丰度以及丝氨酸/苏氨酸磷酸化的差异，在几个亚细胞提取物中，通过应用先进的蛋白质组学技术。 我们的目标是确定肝脏组织中控制脂质和葡萄糖代谢的关键分子途径。 这些研究有可能促进发现新的治疗靶点，降低胰岛素抵抗，避免或改善2型糖尿病。 蛋白质组学数据将为NIH R 01申请以及未来的出版物提供初步数据。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The medio-basal hypothalamus (MBH) plays a pivotal role in the control of hepatic glucose homeostasis. The MBH senses circulating nutrients like glucose and fatty acids as well as hormones like leptin and insulin and thus assesses the energy state of the organism. When circulating levels of nutrients and insulin are rising during the postprandial state, pathways descending from the MBH are activated and hepatic glucose production (hGP) is suppressed. In the insulin resistant (IR) state insulin fails to suppress hepatic glucose production (hGP) which is partly explained by a loss of the MBH control of hGP. The molecular events that take place in peripheral tissues by the activation of these central pathways are poorly understood. The overall goal of this proposal is to utilize high sensitivity, high resolution LC-MS quantitative proteomics from the resource to identify differences in protein levels in total tissue as well as subcellular compartments (including cytosolic, mitochondria and membrane fractions) that are induced by the activation of the MBH. We aim to identify differences in protein abundances as well as serine/threonine phosphorylation differences in several subcellular extracts by applying the advanced proteomics technologies. Our goal is to identify key molecular pathways in liver tissue that exert control of lipid and glucose metabolism. These studies have the potential to facilitate the discovery of new therapeutic targets that decrease insulin resistance and avert or ameliorate type 2 diabetes. The proteomic data will serve the preliminary data for NIH R01 application as well as for future publications.