Nutrient Signals and Programming of Pancreas Development

描述(由申请人提供)：在人类和动物模型中的广泛流行病学证据表明，母亲营养不良会增加子女患2型糖尿病的易感性。细胞发育的改变，导致长期的细胞质量和功能缺陷，是这种表型的主要组成部分。这些观察证实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经被证明，但营养信号如何调节胰腺的分化程序还不完全清楚。这项建议的目的是确定mTOR信号在细胞发育和通过营养信号编程中的作用。有待检验的中心假设是，作用于mTOR的营养信号通过调节胰腺前体细胞的增殖和存活来调节细胞发育和糖尿病的易感性。这将通过以下方法进行检验：具体目标1和2直接解决不同的营养信号如何通过mTOR作用于调节胰腺前体细胞的增殖和存活以及细胞发育。目标3将利用mTOR功能的获得和丢失的可诱导模型，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。在发育的不同阶段，瞬时抑制mTOR信号的长期代谢效应将建立关键窗口。在关键发育期通过瞬时激活mTOR信号来抢救生长迟缓胎儿的高血糖也将进行。这些研究将加强我们对控制胰腺发育的分子机制的理解，以及营养信号对细胞编程的长期代谢影响。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，并为治疗目的调节胰腺前体细胞的分化程序。最后，了解与胎儿宫内发育迟缓相关的糖耐量异常的病理生理学对于预防和治疗都很重要。 与公共卫生相关：不良的宫内环境增加患糖耐量低减和2型糖尿病的易感性的机制尚不清楚，但已经描述了对细胞的一种初级发育侮辱。这项应用的目的是阐明通过营养信号调节胰腺发育和细胞编程的机制，以努力开发预防生长迟缓胎儿糖尿病的策略，并确定改善细胞质量和功能的药物靶点。

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. PUBLIC HEALTH RELEVANCE: The mechanisms by which adverse intrauterine environment increases the susceptibility to develop glucose intolerance and type 2 diabetes are not well understood but a primary developmental insult to the ¿-cell has been described. The goal of this application is to elucidate the mechanisms responsible for regulating pancreas development and ¿-cell programming by nutrient signals in an effort to develop strategies to prevent diabetes in growth retarded fetuses and to identify pharmacological targets to improve ¿-cell mass and function.