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The Role of Intestinal Hypoxia Signaling in Glucose Homeostasis

肠道缺氧信号在血糖稳态中的作用

基本信息

批准号：
9765308
负责人：
Sadeesh Kumar Ramakrishnan
金额：
$ 24.24万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9765308
关键词：
Advisory Committees Affect Area Beta Cell Blood flow Cell physiology Cells Chemosensitization Communication Complex Data Desire for food Diabetes Mellitus Diet Disease Economic Burden Environment Epithelial Fatty acid glycerol esters Foundations Gastric Emptying Genes Genetic Genetic Models Glucagon Glucose Glucose Intolerance Goals Health Homeostasis Hormone secretion Hormones Human Hyperglycemia Hypoxia Hypoxia Inducible Factor In Vitro Inflammation Intervention Intestinal Hormones Intestines Iron Knowledge Leadership Link Malignant Neoplasms Mediating Mentors Mentorship Metabolic Metabolic Diseases Metabolism Michigan Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Operative Surgical Procedures Organ Oxygen Pancreas Pathogenesis Patients Pharmacology Phase Physiology Play Protein Isoforms Regimen Regulation Research Research Design Research Project Grants Resources Role Scientist Signal Transduction Testing Therapeutic Tissues Training Activity United States Universities Work base blood glucose regulation career development detection of nutrient experience feeding glucagon-like peptide 1 glucose metabolism glucose tolerance improved in vivo innovation insulin secretion microbial mouse model new therapeutic target novel programs response skills therapeutic target transcription factor

项目摘要

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.

项目描述