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(由申请者提供)：这份申请的目标是为Linnemann博士提供一个全面的5年培训计划，使她能够成为一名独立的学术科学家。通过这个项目，她将在胰岛细胞生物学、活体生理学、肥胖和代谢途径等领域获得宝贵的研究经验。Dawn Belt Davis博士和Michael MacDonald博士将担任她事业和科学发展的主要共同导师。戴维斯博士是糖尿病和肥胖症研究领域的新兴领导者。麦克唐纳博士是糖尿病和新陈代谢领域公认的领导者，在指导基础和临床科学家方面有着良好的记录。林内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指导。她的指导委员会包括文森特·克里恩斯博士、莫莉·卡恩斯博士和米歇尔·金普尔博士。该研究计划涉及在肥胖环境中保护胰岛β细胞免受细胞凋亡的研究。肥胖与全身炎症和循环细胞因子如白介素6(IL-6)的增加有关。然而，关于IL-6在肥胖状态中的具体作用，有相互矛盾的证据。初步数据表明，循环中的IL-6启动了胰岛内经典胃肠激素的级联产生，即GLP-1和CCK，它们调节β细胞的存活，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刺激适应性应激反应，促进β细胞功能和质量调节。这一应用的具体目的包括1)确定多组分IL-6驱动的途径如何调节β细胞的存活；2)确定IL-6在肥胖驱动的β细胞质量调节中的体内作用。总而言之，这些目标将使我们能够识别一条保护β细胞免受凋亡的新途径，该途径可能成为帮助β细胞大量扩增的治疗靶点。