Notch Signaling Regulates Pituitary Organogenesis

描述（由申请人提供）：脑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、代谢和应激反应。细胞分裂和分化之间的微妙平衡，部分由激素环境调节，决定了脑垂体的大小。除了胚胎发生外，对控制祖细胞行为的分子途径以及垂体细胞数量的分子途径缺乏了解。必须填补这一知识空白，因为垂体疾病表现为激素产生细胞过少（垂体功能减退症）和细胞过多（腺瘤），这是一个巨大的健康负担，仅腺瘤的患病率就为1/1，100。长期目标是确定控制垂体前体细胞增殖的信号通路，以了解垂体功能减退和垂体肿瘤背后的病理学。本申请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其扩增和分化的信号。中心假设是，Notch信号在垂体祖细胞是必要的，以维持他们在一个未分化的状态，并促进他们的增殖，在特定的方式。来自申请人实验室的初步和公开数据支持Notch信号传导的拟议作用。Notch是垂体祖细胞行为的组成部分的假设将通过追求三个具体目标进行测试：1）确定 出生后脑垂体扩张期间控制祖细胞维持和分化之间平衡的机制。2)确定祖细胞在成年脑垂体中维持和动员的机制。3)阐明内源性激素反馈回路如何改变垂体细胞的增殖。在这些目标中的每一个中，将在Notch信号传导的功能的时间控制的获得和丧失的背景下在体内评估垂体祖细胞的增殖和分化。干/祖细胞在出生后和成人垂体只是最近才被描述。这项拟议的研究将促进对整合控制这些祖细胞活性的信号通路的理解。基于靶向Notch信号传导的疗法正处于白血病和乳腺癌的早期临床试验阶段的事实， 理解Notch在垂体祖细胞中的作用，从而导致垂体肿瘤的治疗。

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.