Nutrient Signals and Programming of Pancreas Development

描述（由申请人提供）：在人类和动物模型中广泛的流行病学证据表明，母亲营养不良会增加后代患2型糖尿病的易感性。细胞发育的改变，导致细胞质量和功能的长期缺陷是这种表型的主要组成部分。这些观察发现了胎儿细胞编程的现象。虽然营养在细胞发育过程中作为糖尿病风险的重要性已被证明，但营养信号如何调节胰腺的分化程序尚不完全清楚。本提案的目的是确定mTOR信号在细胞发育和营养信号编程中的作用。要验证的中心假设是，作用于mTOR的营养信号通过调节胰腺祖细胞的增殖和存活来调节细胞发育和对糖尿病的易感性。具体目标1和2直接解决通过mTOR作用的不同营养信号如何调节胰腺祖细胞的增殖和存活以及细胞发育。Aim 3将使用具有mTOR功能获得和丧失的诱导模型，确定mTOR信号调节细胞编程和糖尿病易感性的关键发育窗口。在不同发育阶段，短暂抑制mTOR信号的长期代谢效应将建立关键窗口。在发育的关键时期，通过mTOR信号的短暂激活来拯救生长迟缓胎儿的高血糖也将被执行。这些研究将增强我们对控制胰腺发育的分子机制和营养信号对细胞编程的长期代谢后果的理解。这些信息可用于设计新的治疗方法，以改善糖尿病患者的细胞质量和功能，并调节胰腺祖细胞的分化程序，以达到治疗目的。最后，了解与宫内生长迟缓个体相关的葡萄糖耐受不良的病理生理对预防和治疗都很重要。

DESCRIPTION (provided by applicant): 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 ¿-cell development, leading to long-term defects in ¿-cell mass and function is a major component of this phenotype. These observations identified the phenomena of fetal ¿-cell programming. Although the importance of nutrition during ¿-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 ¿-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 ¿- cell programming by nutrient signals. This information can be used to design novel therapeutic approaches to improve ¿-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.