Obesity induced cytokines and beta cell mass regulation

肥胖诱导的细胞因子和β细胞质量调节

• 批准号: 9211315
• 负责人: Amelia K Linnemann
• 金额: $ 16.3万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9211315
• 关键词: Adult; Affect; Alpha Cell; Apoptosis; Apoptotic; Beta Cell; Biological Assay; Biological Preservation; Cell Survival; Cell physiology; Cells; Cellular Stress; Cellular biology; Chemicals; Cholecystokinin; Clinical; Conflict (Psychology); Cytoprotection; Data; Development; Diabetes Mellitus; Diabetes prevention; Disease; Dose; Environment; Event; Future; GLP-I receptor; Genes; Genetic Transcription; Glucose; Goals; High Fat Diet; Hormones; In Vitro; Individual; Inflammation; Insulin Resistance; Interleukin 6 Receptor; Interleukin-6; Islet Cell; Islets of Langerhans; Knock-out; Knockout Mice; Knowledge; Literature; LoxP-flanked allele; Maintenance; Maps; Mediating; Mentors; Metabolic Pathway; Metabolism; Mollies; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Peripheral; Physiology; Prevalence; Production; Regulation; Research; Role; Scientist; Signal Transduction; Streptozocin; Stress; Structure of beta Cell of islet; Testing; Therapeutic Intervention; Thinness; Time; Training Programs; United States; Work; base; biological adaptation to stress; career; career development; cytokine; experience; glucagon-like peptide 1; in vivo; inflammatory marker; insulin secretion; insulin signaling; interest; interleukin-6 receptor alpha; islet; new therapeutic target; novel; prevent; programs; public health relevance; response; stressor; therapeutic target; transcriptome; transcriptome sequencing

 DESCRIPTION (provided by applicant): The goal of this application is to provide Dr. Linnemann with a comprehensive 5-year training program that will allow her to emerge as an independent academic scientist. Through this program she will gain valuable research experience in the fields of islet cell biology, in vivo physiology, obesity, and metabolic pathways Dr. Dawn Belt Davis and Dr. Michael MacDonald will serve as the primary co- mentors for her career and scientific development. Dr. Davis is an emerging leader in the field of diabetes and obesity research. Dr. MacDonald is an established leader in diabetes and metabolism and has a proven track record of mentoring both basic and clinical scientists. Dr. Linnemann has also assembled a mentoring committee comprised of outstanding scientists to provide the full spectrum of career development and scientific guidance. Her mentoring committee includes Dr. Vincent Cryns, Dr. Molly Carnes, and Dr. Michelle Kimple. The research plan involves the study of pancreatic beta cell protection from apoptosis in an obese environment. Obesity is associated with generalized inflammation and an increase in circulating cytokines such as interleukin-6 (IL-6). However, there is conflicting evidence as to the specific role of IL-6 in an obese state. Preliminary data suggests that circulating IL-6 initiates a cascade of intra-islet production of classic gut hormones, namely GLP-1 and cholecystokinin (CCK), that modulate beta cell survival and thus islet mass. Taking this into account, the central hypothesis is that obesity driven IL-6 stimulates adaptive stress response that promotes beta cell function and mass regulation. The specific aims of this application include 1) To determine how a multicomponent IL-6 driven pathway regulates beta cell survival; and 2) To define the in vivo role of IL-6 in obesity driven beta cell mass regulation. Together, these aims will allow the identification of a novel pathway in the protection of beta cells from apoptosis that may serve as a therapeutic target to aid in beta cell mass expansion.

 描述（由申请人提供）：本申请的目标是为 Linnemann 博士提供为期 5 年的综合培训计划，使她能够成为一名独立的学术科学家。通过该计划，她将获得该领域的宝贵研究经验。道恩·贝尔特·戴维斯 (Dawn Belt Davis) 博士和迈克尔·麦克唐纳 (Michael MacDonald) 博士将担任她的职业和科学发展的主要导师。戴维斯博士是糖尿病和糖尿病领域的新兴领导者。肥胖麦克唐纳博士是糖尿病和代谢领域公认的领导者，在指导基础和临床科学家方面拥有良好的记录，林尼曼博士还组建了一个由杰出科学家组成的指导委员会，提供全方位的职业发展和科学服务。她的指导委员会包括 Vincent Cryns 博士、Molly Carnes 博士和 Michelle Kimple 博士。该研究计划涉及肥胖环境中胰腺 β 细胞保护细胞凋亡与全身性炎症和炎症增加之间的关系。循环然而，关于 IL-6 在肥胖状态下的具体作用，存在相互矛盾的证据，表明循环中的 IL-6 会启动胰岛内一系列经典细胞因子的产生。肠道激素，即 GLP-1 和胆囊收缩素 (CCK)，可调节 β 细胞存活并从而调节胰岛质量，考虑到这一点，中心假设是肥胖驱动的 IL-6 会刺激适应性应激反应，从而导致应激反应。促进 β 细胞功能和质量调节 该应用的具体目的包括 1) 确定多组分 IL-6 驱动途径如何调节 β 细胞存活；以及 2) 确定 IL-6 在肥胖驱动的 β 细胞中的体内作用。总之，这些目标将允许识别保护 β 细胞免于凋亡的新途径，该途径可以作为帮助 β 细胞质量扩张的治疗靶标。