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

项目摘要 这项建议勾勒出了一个为期5年的计划，以提供培训，以发展独立的 从事葡萄糖动态平衡中枢和外周综合调节研究的学术生涯。 候选人已经通过完成医学博士学位和临床培训为这一途径做好了准备 儿科学和胃肠病学。从毕业到毕业，他在所有级别的培训中都取得了科学成果。 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·施瓦茨博士的实验室进行，他是一名 下丘脑对能量平衡和葡萄糖稳态的调节。它将由一位专家监督 由内分泌科的两名成员(格雷戈里·莫顿博士和约书亚博士)组成的指导委员会 Thaler)以及外部顾问(范德比尔特大学的David Wasserman博士)。全面的 培训计划包括继续教育使用同位素技术和分析方法进行研究 从基因到整个生物体水平的葡萄糖动态平衡和代谢的调节。 该提案的重点是有证据表明，成纤维细胞生长因子(FGF)家族的成员发挥了关键作用 通过靶向下丘脑的糖调节神经回路来调节葡萄糖的稳态。vbl.使用 复杂的代谢表型，候选人证明了一次中心注射FGF1 在糖尿病啮齿动物模型中诱导糖尿病高血糖持续缓解。抗糖尿病的效果是 并不次于减肥，也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增加的动物中丧失 初步数据表明，先前对脑脊液FGF1有反应的动物的糖尿病复发与 伴有进行性胰腺β细胞功能障碍。这项研究将描述ICV FGF1通过2个特异性靶点诱导糖尿病高血糖的缓解。在目标1中，我们将描述 介导慢性粒细胞白血病持续缓解的特定受体、细胞内信号级联和突触变化 脑室注射FGF1引起的糖尿病高血糖。目标2侧重于对完整的基础胰岛素的需求 FGF1诱导糖尿病高血糖缓解的信号及FGF1诱导糖尿病的程度 缓解归因于基础胰岛素分泌增加，这是由于保留了胰腺β细胞的功能。 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 新陈代谢的神经调节的生理学使他有资格进行这方面的研究 求婚。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FGF1的翻译潜力 中心靶向FGF1和相关的多肽作为降糖剂。

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.