CNS NFkappaB Regulation of Glucose Homeostasis

描述（由申请人提供）：肥胖在三分之一的美国成年人和儿童中普遍存在，每年花费美国医疗保健系统数十亿美元。肥胖对患者的主要影响是肥胖相关合并症的发展，如2型糖尿病（T2DM）。鉴于肥胖给社会带来的巨大成本，以及这些疾病对患者的影响，建立肥胖和2型糖尿病之间的联系对于有效治疗和降低2型糖尿病的患病率至关重要。肥胖和2型糖尿病之间联系的可能机制之一是通过炎症途径。越来越多的证据表明，中枢神经系统对调节葡萄糖稳态的激素和营养物质有反应，并且该系统的失调可能发生在NF？B激活。然而，尚未研究中枢神经系统对该途径对外周代谢过程的潜在调节。在这个提案中，西斯莱博士将重点研究一种特定的脑炎症途径NF？B，葡萄糖稳态。她的初步数据显示，单剂量的NF？B抑制剂改善葡萄糖耐量。她的提案的具体目的是研究中枢神经系统抑制NF？B途径对葡萄糖稳态的急性抑制研究。她还将研究CNS - NF？B外周组织炎症标志物的抑制作用。这个导师奖学金的主要目标是推动Sisley博士在追求独立研究生涯中前进。

DESCRIPTION (provided by applicant): Obesity is prevalent in one third of American adults and children and costs the American health care system billions of dollars yearly. The major impact of obesity on patients is the development of obesity-related comorbidities, such as type 2 diabetes mellitus (T2DM). Given the extensive cost to society, as well as the impact of these conditions on patients, establishing the link between obesity and T2DM is paramount to effectively treating and decreasing the prevalence of T2DM. One of the possible mechanisms linking obesity and T2DM is through inflammatory pathways. Accumulating evidence indicates that the CNS is responsive to hormones and nutrients regulating glucose homeostasis and that dysregulation of this system may occur with NF?B activation. However, the potential CNS regulation of this pathway on peripheral metabolic processes has not been studied. In this proposal, Dr. Sisley will focus on the effect of one specific brain inflammatory pathway, NF?B, on glucose homeostasis. Her preliminary data have revealed the ability of a single dose of an NF?B inhibitor to improve glucose tolerance. The specific aims of her proposal will examine the mechanistic link between CNS inhibition of the NF?B pathway on glucose homeostasis using acute inhibition studies. She will also investigate the effect of CNS NF?B inhibition on inflammatory markers in peripheral tissues. The primary goal of this mentored fellowship award is to advance Dr. Sisley forward in her pursuit of an independent research career.