CNS NFkappaB Regulation of Glucose Homeostasis

肥胖症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，例如2型糖尿病（T2 DM）。考虑到社会的广泛成本以及这些疾病对患者的影响，建立肥胖和T2DM之间的联系对于有效治疗和降低T2DM的患病率至关重要。肥胖和T2DM之间的可能机制之一是通过炎症途径。越来越多的证据表明，中枢神经系统是响应激素和营养调节葡萄糖稳态和失调，这一系统可能会发生NF？B激活。然而，尚未研究该途径对外周代谢过程的潜在CNS调节。在这项提案中，博士西斯利将集中在一个特定的大脑炎症通路，NF？B，葡萄糖稳态。她的初步数据显示单剂量NF？B抑制剂改善葡萄糖耐量。她的建议的具体目标将研究中枢神经系统抑制NF？B途径对葡萄糖稳态的影响。她还将研究中枢神经系统NF？B对外周组织中炎性标志物的抑制。这个指导奖学金的主要目标是推进博士Sisley在她追求独立的研究生涯前进。

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.