SIRT1 介导的 Notch/Hes1 信号改变对小于胎龄儿下丘脑神经前体细胞发育影响的研究

小于胎龄儿（SGA）在生长期食欲明显增加，导致成年后肥胖患病率增高。下丘脑神经前体细胞（NPCs）在特定条件下，发育为调控食欲的神经元NPY和POMC。Hes1是促进NPCs增殖而抑制其过早分化的重要因子并受Notch调节,上调的SIRT1通过静默Hes1对Notch的反应，抑制NPCs增殖促进其过早分化，继而影响调控食欲神经元的发育。目前SGA下丘脑NPCs发育调控异常的信号机制尚不清楚。我们前期研究发现SGA下丘脑促进食欲神经元NPY增加，抑制食欲神经元POMC减少；SIRT1表达增加，Hes1和Notch表达下降。本项目应用下丘脑神经球培养以及体内\体外动物模型，探讨SIRT1介导的Notch/Hes1信号变化是否导致SGA的NPCs程序性增殖与分化发生改变，最终影响调控食欲神经元的发育。本研究希望揭示SGA下丘脑神经前体细胞发育编程信号机制，为研究SGA成年发生肥胖病因学提供依据。

A newly recognized ,primary cause of the metabolic syndrome epidemic is the developmental programming effects of the in utero environment.Human small for gestational age(SGA) infants are markedly increased risk of childhood and adult obesity.Together with evidence that SGA offspring have reduced anorexigenic neural pathway development, these findings indicate that altered hypothalamic neurodevelopment represents a putative mechanism for programmed obesity.We have demonstrated that hypothalamic neuronal progenitor cell(NPCs) from SGA fetuses and newborns exhibit programmed dysfunction of proliferation and differentiation under basal and neurotrophic stimulated conditions. The bHLH protein Hes1,is a primary factor which promotes NPC self-renewal while inhibiting differentiation. Hes1 expression is stimulatedfollowing activation of the transmembrane protein Notch1,and inhibited by epigenetic actions of the nutrient sensor, SIRT1, a histone deacetylase. We propose that as a result of impaired in utero nutrition, reduced Hes1 expression in SGA offspring impairs NPC proliferation/selfrenewal, reducing the NPC pool. Consistent with this hypothesis, our studies have confirmeddownregulation of Notch and Hes1, and upregulation of SIRT1 in SGA NPCs.Thus, dysfunctional hypothalamic neuronal development is a consequence of both (1): a reduction in the NPC pool, and (2):reduced neurotrophic factors during critical fetal/neonatal periods. This project will examine the putative mechanisms for the programming of hypothalamic NPC,using both neurosphere culture and in vivo/ex vivorodent studies.Neurogenesis and cell composition of hypothalamic orexigenic-regulatory nuclei will be studied in SGA and control offspring, and we will delineate epigenetic mechanisms which underpin reduced proliferation. This proposal provides a unique opportunity to determine mechanisms of programmed neurogenic dysfunction in SGA offspring which contribute to offspring obesity.