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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该提案描绘了一个为期 5 年的计划，旨在提供培训，以发展独立的学术研究生涯主要研究葡萄糖稳态的中枢和外周综合调节。候选人已通过完成医学博士和博士学位以及临床培训为该途径做好准备通过研究生学习，他在儿科和胃肠病学的各个级别的培训中都取得了科学的成果。和博士后工作，撰写论文 15 篇（其中 7 篇为第一或共同第一作者），并成功竞争美国心脏协会和美国国立卫生研究院的奖学金。拟议的研究将在迈克尔·施瓦茨博士（Michael Schwartz）的实验室进行，他是该领域的专家下丘脑对能量平衡和葡萄糖稳态的调节将由专家监督。由内分泌科两名成员（Gregory Morton 博士和 Joshua 博士）组成的指导委员会 Thaler）以及外部顾问（范德堡大学 David Wasserman 博士）。培训计划包括使用同位素技术和分析方法进行研究的继续教育从基因到整个有机体水平的葡萄糖稳态和代谢的调节。该提案重点关注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来调节葡萄糖稳态。通过复杂的代谢表型分析，候选人证明单次中央注射 FGF1 在糖尿病啮齿动物模型中诱导糖尿病高血糖的持续缓解。不是继发于体重减轻，并且与胰岛素敏感性增加无关。 icv FGF1诱导糖尿病缓解的能力在严重胰岛素缺乏和额外的动物中丧失初步数据表明，先前对 icv FGF1 有反应的动物的糖尿病复发与进行性胰腺 β 细胞功能障碍本研究将描述 ICV 的机制。 FGF1 通过 2 个具体目标诱导糖尿病高血糖的缓解在目标 1 中，我们将描述其特征。特异性受体、细胞内信号级联和突触变化介导持续缓解 icv FGF1 引起的糖尿病高血糖目标 2 侧重于完整基础胰岛素的需求。 FGF1 诱导糖尿病高血糖缓解的信号以及 FGF1 诱导糖尿病的程度缓解可归因于胰腺β细胞功能的保留导致基础胰岛素分泌增加。申请人综合了神经解剖学、分子生物学、组织化学、药理学方面的专业知识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这些研究的结果预计将为未来的研究提供令人信服的理由。研究 FGF1 介导的糖尿病缓解机制，探索其转化潜力中枢靶向 FGF1 和相关肽作为抗糖尿病药物。