Central and Peripheral Mechanisms of FGF1-Mediated Remission of Diabetic Hyperglycemia

FGF1介导缓解糖尿病高血糖的中枢和外周机制

• 批准号: 9370073
• 负责人: Jarrad M Scarlett
• 金额: $ 16.38万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9370073
• 关键词: American Heart Association; Animals; Antidiabetic Drugs; Apoptosis; Area; Beta Cell; Binding; Biochemical; Biological Preservation; Blood Circulation; Blood Glucose; Body Weight; Body Weight decreased; Brain; Cell Nucleus; Cell Proliferation; Cell physiology; Characteristics; Clinical; Closure by clamp; Complex; Continuing Education; DNA biosynthesis; Data; Deterioration; Development; Diabetes Mellitus; Disease remission; Doctor of Philosophy; Dose; Eating; Economic Burden; Educational Status; Endocrinology; FGF1 gene; FGFR1 gene; Family; Fellowship; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Fibrosis; Functional disorder; Future; Gastroenterology; Gene Targeting; Genes; Genetic; Glucose; Goals; Heparin; Histocytochemistry; Human; Hyperglycemia; Hypoglycemia; Hypothalamic structure; Immunohistochemistry; Impairment; Injection of therapeutic agent; Insulin; Integrins; Islets of Langerhans; Isotopes; Laboratories; Light; Link; MAP Kinase Gene; Manuscripts; Mediating; Mentors; Metabolism; Modification; Molecular Biology; Neuroanatomy; Neuronal Injury; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Outcome Study; Pathway interactions; Pediatrics; Peptides; Peripheral; Pharmacology; Physiology; Play; Prevalence; Principal Investigator; Rattus; Receptor Signaling; Regulation; Relapse; Reporting; Research; Rodent Model; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Structure; Structure of beta Cell of islet; Synapses; Synaptophysin; Techniques; Therapeutic; Training; United States National Institutes of Health; Universities; Unspecified or Sulfate Ion Sulfates; Whole Organism; Work; analytical method; basal insulin; base; blood glucose regulation; career; cell type; diabetic; energy balance; glucose metabolism; improved; insulin secretion; insulin sensitivity; insulin signaling; interest; islet; member; metabolic phenotype; mutant; neuroregulation; non-diabetic; pancreatic islet function; prevent; programs; protein biomarkers; receptor; receptor binding; response; stem; time interval; transcriptomics

Project Summary This proposal delineates a 5-year program to provide training toward the development of an independent academic research career in the study of integrated central and peripheral regulation of glucose homeostasis. The candidate has been prepared for this pathway by completing MD and PhD degrees and clinical training in Pediatrics and Gastroenterology. He has been scientifically productive at all levels of training through graduate and postdoctoral work, contributing to 15 manuscripts (7 of them first or co-first author), and successfully competing for fellowships from the American Heart Association and the NIH. The proposed research will be conducted in the laboratory of Dr. Michael Schwartz, an expert in the field of hypothalamic regulation of energy balance and glucose homeostasis. It will be overseen by an expert mentoring committee with two members of the Endocrinology Division (Dr. Gregory Morton and Dr. Joshua Thaler) as well as an external advisor (Dr. David Wasserman, Vanderbilt University). The comprehensive training plan involves continued education in the use of isotopic techniques and analytical methods to study regulation of glucose homeostasis and metabolism from the gene to the whole organism level. The proposal focuses on evidence that members of the fibroblast growth factor (FGF) family play a key role in the regulation of glucose homeostasis by targeting hypothalamic glucoregulatory neurocircuits. Using sophisticated metabolic phenotyping, the candidate demonstrated that a single central injection of FGF1 induces sustained remission of diabetic hyperglycemia in rodent models of diabetes. The anti-diabetic effect is not secondary to weight loss, and is not associated with an increase in insulin sensitivity. Furthermore, the ability of icv FGF1 to induce diabetes remission is lost in animals with severe insulin deficiency and additional preliminary data suggest that relapse of diabetes in animals previously responsive to icv FGF1 is associated with progressive pancreatic β-cell dysfunction. This research will characterize the mechanisms by which icv FGF1 induces remission of diabetic hyperglycemia through 2 specific aims. In Aim 1, we will characterize the specific receptors, intracellular signaling cascades, and synaptic changes that mediate sustained remission of diabetic hyperglycemia in response to icv FGF1. Aim 2 focuses on the requirement of an intact basal insulin signal for FGF1 to induce remission of diabetic hyperglycemia and the extent to which FGF1-induced diabetes remission is attributable to increased basal insulin secretion due to preservation of pancreatic β-cell function. The applicant's combination of expertise in neuroanatomy, molecular biology, histochemistry, pharmacology and physiology of the neural regulation of metabolism uniquely qualify him to conduct the studies in this proposal. Outcomes from these studies are expected to provide a compelling rationale for future studies investigating the mechanisms of FGF1-mediated diabetes remission, exploring the translational potential for centrally-targeted FGF1 and related peptides as anti-diabetic agents.

项目摘要 该提案描绘了一个5年计划，以提供培训，以发展一个独立的 学术研究生涯中的综合中枢和外周调节葡萄糖稳态的研究。 候选人已经通过完成MD和PhD学位和临床培训为这一途径做好了准备， 儿科和胃肠病学。他一直在科学生产的各级培训，通过研究生 和博士后工作，贡献了15篇手稿（其中7篇是第一作者或共同第一作者），并成功地 竞争美国心脏协会和国家卫生研究院的奖学金。 拟议的研究将在迈克尔施瓦茨博士的实验室进行，他是该领域的专家。 下丘脑调节能量平衡和葡萄糖稳态。它将由一位专家监督 由内分泌科的两名成员（Gregory Morton博士和约书亚博士）组成的指导委员会 Thaler）以及外部顾问（范德比尔特大学的大卫沃瑟曼博士）。综合 培训计划包括使用同位素技术和分析方法的继续教育， 从基因到整个机体水平对葡萄糖稳态和代谢的调节。 该提案的重点是成纤维细胞生长因子（FGF）家族成员发挥关键作用的证据 通过靶向下丘脑葡萄糖调节神经回路调节葡萄糖稳态。使用 复杂的代谢表型，候选人证明，单一的中央注射FGF1， 在啮齿动物糖尿病模型中诱导糖尿病高血糖症的持续缓解。抗糖尿病作用是 不继发于体重减轻，并且与胰岛素敏感性的增加无关。而且 icv FGF 1诱导糖尿病缓解的能力在严重胰岛素缺乏的动物中丧失， 初步数据表明，先前对icv FGF 1有反应的动物的糖尿病复发与 胰腺β细胞功能障碍这项研究将描述icv FGF 1通过2个特定目的诱导糖尿病高血糖缓解。在目标1中，我们将描述 特异性受体、细胞内信号级联和介导持续缓解的突触变化。 糖尿病性高血糖症对icv FGF 1的反应。目标2关注完整基础胰岛素的需求 FGF1诱导糖尿病高血糖缓解的信号和FGF1诱导的糖尿病 缓解可归因于由于胰腺β细胞功能的保留而增加的基础胰岛素分泌。 申请人在神经解剖学、分子生物学、组织化学、药理学方面的专业知识 和新陈代谢的神经调节生理学使他有资格进行这方面的研究。 提议这些研究的结果有望为未来的研究提供令人信服的理论基础 研究FGF1介导的糖尿病缓解机制，探索FGF1的翻译潜力， 作为抗糖尿病剂的中枢靶向FGF 1和相关肽。