Notch Signaling Regulates Pituitary Organogenesis

描述(申请人提供)：脑下垂体通过从少量高度特化的细胞释放激素来协调生长、生育、新陈代谢和应激反应。细胞分裂和分化之间的微妙平衡，部分受荷尔蒙环境的调节，决定了脑下垂体的大小。除了胚胎发生外，对于控制前体细胞行为的分子途径，从而控制垂体细胞数量的分子途径，还缺乏了解。必须填补这一认识空白，因为垂体疾病表现为产生激素的细胞太少(垂体腺功能减退)，而细胞(腺瘤)太多，构成了巨大的健康负担，仅腺瘤的患病率就高达1/1100。长期的目标是确定控制垂体前体细胞增殖的信号通路，以了解垂体功能低下和垂体肿瘤背后的病理机制。这项应用的目的是确定垂体祖细胞/干细胞在出生后和成年腺体中维持的机制，以及控制它们扩张和分化的信号。中心假说是，脑下垂体前体细胞中的Notch信号是维持其处于未分化状态并以特定的方式促进其增殖所必需的。来自申请者实验室的初步和公布的数据支持Notch信号的拟议作用。Notch是垂体祖细胞行为的一个组成部分的假设将通过追求三个特定目标来检验：1)确定 在出生后的脑下垂体扩张过程中控制祖细胞维持和分化之间的平衡的机制。2)确定成体脑下垂体内祖细胞维持和动员的机制。3)阐明内源性激素反馈环如何改变垂体细胞的增殖。在上述每个目标中，垂体祖细胞的增殖和分化将在时间受控的Notch信号获得和功能丧失的背景下在体内进行评估。出生后和成年脑下垂体中的干细胞/祖细胞直到最近才被描述。这项拟议的研究将促进对信号通路的理解，这些信号通路整合在一起控制这些祖细胞的活动。基于针对Notch信号转导的治疗处于白血病和乳腺癌的早期临床试验阶段的事实，基本的 了解脑下垂体前体细胞的Notch作用有助于脑垂体肿瘤的治疗。

DESCRIPTION (provided by applicant): The pituitary gland coordinates growth, fertility, metabolism and the stress response through release of hormones from small numbers of highly specialized cells. A delicate balance between cell division and differentiation, in part regulated by hormonal milieu, dictates pituitary gland size. There is a lack of understanding of the molecular pathways controlling progenitor cell behavior, and thus pituitary cell number, beyond embryogenesis. This gap in knowledge must be filled because pituitary diseases presenting with too few hormone producing cells (hypopituitarism) and too many cells (adenomas) represent a substantial health burden, with the prevalence of adenomas alone being 1 in 1,100. The long-term goal is to define the signaling pathways controlling proliferation of pituitary progenitor cels to understand the pathology behind hypopituitarism and pituitary tumors. The objective of this application is to determine the mechanism by which pituitary progenitor/stem cells are maintained in the postnatal and adult gland and the signals that control their expansion and differentiation. The central hypothesis is that Notch signaling in pituitary progenitors is necessary to maintain them in an undifferentiated state and to promote their proliferation in a context specific manner. Preliminary and published data from the applicant's lab support the proposed role of Notch signaling. The hypothesis that Notch is an integral component of pituitary progenitor cell behavior will be tested by pursuing three specific aims: 1) Determine the mechanism by which the balance between progenitor maintenance and differentiation is controlled during pituitary gland expansion after birth. 2) Determine the mechanism by which progenitor cells are maintained and mobilized in the adult pituitary gland. 3) Elucidate how endogenous hormone feedback loops can alter proliferation of pituitary cells. In each of these aims, proliferation and differentiation of pituitary progenitor cells will be assessed in vivo in te context of temporally controlled gain and loss of function of Notch signaling. Stem/progenitor cells in the postnatal and adult pituitary have only recently been described. This proposed research would advance the understanding of signaling pathways that integrate to control the activity of these progenitor cells. Based on the fact that therapies targeting Notch signaling are in early stage clinical trials for leukemia and breast cancer, there is the potential for the basic understanding of Notch action in pituitary progenitors to lead to treatment of pituitary tumors.