Notch Signaling Regulates Pituitary Organogenesis

Notch 信号调节垂体器官发生

• 批准号: 8703078
• 负责人: LORI T RAETZMAN
• 金额: $ 33.02万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703078
• 关键词: Adrenalectomy; Adult; Affect; Age; Anterior Pituitary Hormones; Birth; Breeding; Cell Count; Cell Differentiation process; Cell Maintenance; Cell division; Cells; Data; Development; Disease; Doxycycline; Embryo; Embryonic Development; Endocrine System Diseases; Equilibrium; Estrogens; Event; Excision; Feedback; Fertility; Functional disorder; Gene Expression; Gland; Goals; Grant; Growth; Health; Hormonal; Hormones; Human; Hydrocortisone; Hyperplasia; Hypopituitarism; Hypothalamic structure; Infertility; Knockout Mice; Knowledge; Lead; Life; Maintenance; Mediating; Metabolism; Modeling; Molecular; Morbidity - disease rate; Mus; Operative Surgical Procedures; Organ; Organ Size; Organogenesis; Pathology; Pathway interactions; Phase I Clinical Trials; Pituitary Diseases; Pituitary Gland; Pituitary Hypoplasia; Pituitary Neoplasms; Plastics; Population; Pregnancy; Prevalence; Publishing; Recurrence; Research; Role; Signal Pathway; Signal Transduction; Stem cells; Testing; Undifferentiated; Work; adenoma; base; biological adaptation to stress; cell behavior; cofactor; growth hormone-releasing hormone receptor; in vivo; leukemia; loss of function; loss of function mutation; malignant breast neoplasm; mortality; notch protein; postnatal; prevent; progenitor; programs; protein expression; public health relevance; stem; tumor; tumor growth

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.

描述（由申请人提供）：垂体辅助生长，生育能力，代谢和通过从少量高度专业的细胞中释放激素来应对压力反应。细胞分裂与分化之间的微妙平衡部分由荷尔蒙环境调节，决定了垂体的大小。除了胚胎发生以外，对控制祖细胞行为的分子途径以及垂体细胞的数量缺乏了解。必须填补这一知识的差距，因为垂体疾病出现的激素产生细胞太少（低毒素），而太多的细胞（腺瘤）代表了巨大的健康负担，单独的腺瘤患病率是1,100中的1个。长期目标是定义控制垂体祖细胞增殖的信号传导途径，以了解垂体和垂体肿瘤背后的病理。该应用的目的是确定垂体祖细胞/干细胞在产后和成年腺中维持的机制以及控制其扩张和分化的信号。中心假设是，垂体祖细胞中的凹槽信号传导对于将它们保持在未分化状态并以特定方式促进它们的扩散是必要的。来自申请人实验室的初步和已发布的数据支持Notch信号的拟议作用。通过追求三个特定目的，将测试Notch是垂体祖细胞行为不可或缺的假设：1）确定 出生后垂体膨胀期间控制祖细胞维持和分化之间平衡的机制。 2）确定在成年垂体中维持和动员祖细胞的机制。 3）阐明内源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，将在时间控制的增益和Notch信号功能丧失的情况下，在体内评估垂体祖细胞的增殖和分化。直到最近才描述了产后和成年垂体中的茎/祖细胞。这项提出的研究将提高对整合以控制这些祖细胞活性的信号通路的理解。基于以下事实，靶向Notch信号传导的疗法是在白血病和乳腺癌的早期临床试验中 了解垂体祖细胞中缺口作用，导致垂体肿瘤的治疗。