Nutrient signals and programming of pancreas development

摘要 人类和动物模型中广泛的流行病学证据表明，母亲营养不良 增加了后代患2型糖尿病的易感性。β细胞发育的改变， 导致β-细胞质量和功能的长期缺陷是这种表型的主要组成部分。这些 观察鉴定了胎儿β细胞编程的现象。虽然营养的重要性， β细胞发育作为糖尿病的风险已被证明，目前还不完全清楚营养信号如何 调节胰腺的分化程序。本建议的目的是确定以下方面的作用： mTOR信号传导对胰岛细胞发育和通过营养信号编程的影响。核心假设是 实验表明，作用于mTOR的营养信号通过以下途径调节胰岛细胞的发育和对糖尿病的易感性： 调节胰腺祖细胞增殖和存活。这将通过以下方法进行测试： 具体目标1和2直接解决了不同的营养信号如何通过mTOR调节 胰腺祖细胞的增殖和存活以及胰岛细胞发育。目标3将确定 - 发育窗口，在此期间mTOR信号传导的调节调节β细胞编程， 使用具有mTOR功能获得和丧失的可诱导模型来评估糖尿病的易感性。长期代谢 在不同发育阶段瞬时抑制mTOR信号传导的作用将建立关键的 窗口通过瞬时激活mTOR信号通路挽救生长迟缓胎儿的高血糖症 关键的发展时期也将进行。这些研究将增进我们对 控制胰腺发育的分子机制和β- 通过营养信号进行细胞编程。这些信息可用于设计新的治疗方法， 改善糖尿病患者的β细胞质量和功能，并调节胰腺癌的分化程序， 用于治疗目的的祖细胞。最后，了解葡萄糖耐受不良的病理生理学 与胎儿宫内发育迟缓相关的基因对于预防和治疗都很重要。

Abstract Extensive epidemiological evidence in humans and animal models suggests that poor maternal nutrition increases the susceptibility of the offspring to develop type-2 diabetes. Alterations in β-cell development, leading to long-term defects in β-cell mass and function is a major component of this phenotype. These observations identified the phenomena of fetal β-cell programming. Although the importance of nutrition during β-cell development as a risk for diabetes has been demonstrated, it is not entirely clear how nutrient signals regulate the differentiation program of the pancreas. The objective of this proposal is to determine the role of mTOR signaling on -cell development and programming by nutrient signals. The central hypothesis to be tested is that nutrient signals acting on mTOR modulate -cell development and susceptibility to diabetes by regulating pancreatic progenitor proliferation and survival. This will be tested by the following approach: Specific Aims 1 and 2 directly address how different nutrient signals acting through mTOR regulate proliferation and survival of pancreatic progenitors and -cell development. Aim 3 will identify the critical developmental window during which modulation of mTOR signaling regulates β-cell programming and susceptibility to diabetes using inducible models with gain and loss of mTOR function. Long-term metabolic effects of transient inhibition of mTOR signaling during different stages of development will establish the critical window. Rescue of hyperglycemia in growth-retarded fetuses by transient activation of mTOR signaling during critical developmental period will also be performed. These studies will enhance our understanding of the molecular mechanisms that govern pancreas development and the long-term metabolic consequences of β- cell programming by nutrient signals. This information can be used to design novel therapeutic approaches to improve β-cell mass and function in diabetics and to modulate the differentiation program of pancreatic progenitors for therapeutic purposes. Finally, understanding the pathophysiology of glucose intolerance associated in individuals with intrauterine growth retardation is important for both prevention and therapy.