The Role of Intestinal Hypoxia Signaling in Glucose Homeostasis

项目说明 肥胖症和2型糖尿病在美国正以惊人的速度增长，需要新药 目标是使这些疾病达到顶峰。胃肠衍生激素胰高血糖素样肽-1(GLP-1)改善血糖 动态平衡，为肥胖症和2型糖尿病的治疗提供了巨大的希望。这个 调节肠道GLP-1分泌的机制尚不清楚。肠的功能是动态的 受肠道氧合的调节。低氧诱导转录介导的低氧反应 低氧诱导因子(HIF)。低氧诱导因子信号在炎症中的关键作用 动态平衡和癌症已经有了很好的记录；然而，它的代谢作用还没有被很好地理解。 利用遗传模型，我们揭示了肠道低氧信号的结构性激活改善了血糖 由于GLP-1水平增加而导致的耐受性。这一应用的研究重点在于交叉口 肠道低氧信号与GLP-1在调节血糖稳态中的作用。我们的中央 假说认为，肠道低氧信号在全身葡萄糖稳态中起关键作用。 调节GLP-1的分泌。我们提出了一个免费的体外和体内小鼠研究相结合的方法。 旨在检验以下假设：1)完整的肠道低氧信号对全身 2)肠道低氧信号通过依赖GLP-1调节糖代谢 机制；3)靶向HIF信号转导改善糖耐量异常。 在这个项目的K99阶段，分子和综合系的Shah博士和Seeley博士 生理学和外科将分别为申请者提供指导。职业生涯 开发活动将利用 密歇根大学，并将在高度积极的 申请者除共同导师外，还包括奥利里、瑞和李博士。申请者体验 在概念知识、研究技能、领导力和实验室管理等几个领域，有效 将通过各种培训活动加强对青年科学家的交流和指导 在申请者职业发展活动中详细说明。

Project Description Obesity and type 2 diabetes are increasing at an alarming rate in the United States and warrants novel drug targets to culminate these diseases. Gut derived hormone glucagon like peptide-1 (GLP-1) improves glucose homeostasis and offers great promises as therapeutic target for obesity and type 2 diabetes. The mechanisms that regulate intestinal GLP-1 secretion are not clear. The function of intestine is dynamically regulated by intestinal oxygenation. Low oxygen induces a hypoxic response mediated by the transcription factors namely hypoxia inducible factor (HIF). The critical role of HIF signaling in inflammation, iron homeostasis, and cancers has been well documented; however, its metabolic role is not well understood. Using genetic model, we reveal that constitutive activation of intestinal hypoxia signaling improves glucose tolerance due to augmented GLP-1 levels. The research focus of this application lies at the intersection between intestinal hypoxia signaling and GLP-1 in the regulation of glucose homeostasis. Our central hypothesis states that intestinal hypoxia signaling plays a key role in systemic glucose homeostasis by regulating GLP-1 secretion. We propose a combination of complimentary in vitro and in vivo mouse studies designed to test the following hypothesis: 1) intact intestinal hypoxia signaling is essential for systemic glucose homeostasis; 2) intestinal hypoxia signaling regulates glucose metabolism through GLP-1 dependent mechanism; and 3) targeting HIF signaling ameliorates glucose intolerance. During the K99 phase of this program, Drs. Shah and Seeley in the Department of Molecular and Integrative Physiology and Department of Surgery, respectively, will provide mentorship to the applicant. The career development activities will take advantage of the exceptional research environment and resources at the University of Michigan, and will be facilitated by the guidance of the highly motivated Advisory Committee of the applicant that includes Drs. Omary, Rui and Lee, in addition to the co-mentors. The applicants experience in several areas such as conceptual knowledge, research skills, leadership and lab management, effective communication, and mentoring young scientists will be strengthened through various training activities as detailed in applicants Career development activity.