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.

项目摘要该提案描述了一项为期5年的计划，以提供独立的培训葡萄糖稳态综合中心和外围调节研究的学术研究职业。候选人是通过完成MD和PhD学位和临床培训来为该途径准备的儿科和胃肠病学。他通过毕业生在各个培训的各个级别上都具有科学生产力和博士后作品，贡献了15个手稿（其中7个第一或联合作者），并成功地竞争美国心脏协会和NIH的奖学金。拟议的研究将在迈克尔·施瓦茨（Michael Schwartz）博士的实验室中进行。下丘脑对能量平衡和葡萄糖稳态的调节。它将由专家监督与内分泌部的两名成员的指导委员会（Gregory Morton博士和Joshua博士 Thaler）以及外部顾问（范德比尔特大学的David Wasserman博士）。综合培训计划涉及继续教育同位素技术和分析方法调节葡萄糖稳态和代谢从基因到整个生物水平的调节。该提案的重点是证据表明成纤维细胞生长因子（FGF）家庭起着关键作用的证据通过靶向下丘脑葡萄糖调节性神经环节来调节葡萄糖稳态。使用软化的代谢表型，候选人表明FGF1的单个中央注入在糖尿病的啮齿动物模型中，诱导糖尿病高血糖的持续缓解。抗糖尿病效应是不是体重减轻的继发性，与胰岛素敏感性的增加无关。此外， 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，以前对ICV FGF1的动物中的糖尿病继电器是相关的进行性胰腺β细胞功能障碍。这项研究将表征ICV的机制 FGF1通过2个特定目的诱导糖尿病高血糖的缓解。在AIM 1中，我们将表征特定受体，细胞内信号传导级联和突触变化，培养基持续缓解响应ICV FGF1的糖尿病高血糖。 AIM 2专注于完整的基本胰岛素的需求 FGF1的信号诱导糖尿病性高血糖的缓解以及FGF1诱导的糖尿病的程度由于保存胰腺β细胞功能，缓解归因于增加的碱性胰岛素分泌。该应用在神经解剖学，分子生物学，组织化学，药理学方面的专业知识结合以及新陈代谢神经调节的生理学独特地使他有资格进行这项研究提议。这些研究的结果有望为未来的研究提供令人信服的理由研究FGF1介导的糖尿病缓解机制，探索翻译的潜力作为抗糖尿病药物的中心靶向FGF1和相关肽。