The Role of Intestinal Hypoxia Signaling in Glucose Homeostasis

项目描述 肥胖和2型糖尿病在美国正以惊人的速度增长，需要新药 目标是消灭这些疾病。肠源性激素胰高血糖素样肽-1（GLP-1）改善血糖 体内平衡，并提供了作为肥胖症和2型糖尿病的治疗靶点的巨大希望。的 调节肠GLP-1分泌的机制尚不清楚。肠的功能是动态的 由肠道氧合调节。低氧诱导转录介导的缺氧反应 缺氧诱导因子（HIF）。HIF信号转导在炎症、铁 体内平衡和癌症已经有很好的记录;然而，它的代谢作用还没有很好地理解。 使用遗传模型，我们揭示了组成性激活肠道缺氧信号改善葡萄糖 由于GLP-1水平增加而产生的耐受性。这一应用的研究重点在于 肠缺氧信号传导和GLP-1在葡萄糖稳态调节中的作用。我们的中央 一种假说认为，肠道缺氧信号在全身葡萄糖稳态中起关键作用， 调节GLP-1分泌。我们提出了一个体外和体内小鼠研究的组合 设计用于测试以下假设：1）完整的肠缺氧信号传导对于全身性缺氧是必需的。 葡萄糖稳态; 2）肠缺氧信号通过GLP-1依赖性调节葡萄糖代谢 机制;和3）靶向HIF信号传导改善葡萄糖耐受不良。 在该计划的K99阶段，分子和综合系的Shah和塞利博士 生理学系和外科系将分别为申请人提供指导。职业 开发活动将利用特殊的研究环境和资源， 密歇根大学，并将通过高度积极的咨询委员会的指导， 申请人，其中包括博士。奥玛丽，芮和李，除了共同导师。申请人经历 在几个领域，如概念知识，研究技能，领导和实验室管理，有效 将通过各种培训活动加强交流和指导青年科学家， 在申请人的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.