Molecular Control of Pituitary Development and Tumorigenesis

垂体腺瘤是人类最常见的肿瘤之一，影响超过15%的 美国的人口。然而，目前还不知道是什么调节了内分泌的分裂。 成人体内的细胞。Hedgehog(HH)/Gli和成纤维细胞生长因子介导的细胞-细胞信号转导在垂体中起关键作用 胚胎发育，这是从鱼类到脊椎动物物种的一种保守要求 对人类来说。我们已经证明，HH/Gli信号在控制细胞的数量和位置方面起着作用。 胚胎中的内分泌细胞类型。对其细胞和分子机制知之甚少。 哪些激素在脑下垂体起作用，或者这些信号系统如何继续影响内分泌细胞 胚胎后分化和增殖。 我们的目标是了解HH诱导脊椎动物和在功能上形成模式的机制 并确定HH/Gli信号如何影响胚胎后脑垂体的生长。 从胚胎角度来说。在目标#1中，我们试图确定两个子域的胚胎起源 并确定胎盘细胞是否直接需要HH/Gli信号，这是一个至关重要的 了解诱导和塑造脑下垂体的细胞和分子机制 腺体。目标2的目标是描述和量化幼虫的内分泌细胞增殖。 并确定HH/Gli信号如何在胚胎后调节内分泌细胞数量。 这些研究旨在洞察这种组织的有序复杂性是如何产生的，如何 产生不同类型的内分泌细胞，以及如何调节垂体的生长和分化。 回答这些问题很重要，尤其是因为许多疾病都起源于 胚胎发育。此时HH信号中的错误，如果不纠正，可能会发展为医疗 无前脑或内分泌功能障碍等情况，包括侏儒症和 垂体功能减退。由于HH抑制剂现在正被用于治疗其他几种人类肿瘤，这 这项工作可能有助于提供所需的分子背景，以将类似的治疗方法带给患有 脑垂体腺瘤。 评论[MB1]：我假设STAT在美国？ 考虑到你正在申请，我会在这里加上美国 为了小灵通的钱。

Pituitary adenomas are among the most prevalent of human tumors, affecting over 15% of the population in the United States. However, it is not yet known what regulates the division of endocrine cells in adults. Hedgehog (Hh)/Gli and Fgf-mediated cell-cell signaling play critical roles in pituitary development in the embryo, a requirement that has been conserved across vertebrate species from fish to humans. We have shown that Hh/Gli signaling plays a role in controlling the number and position of endocrine cell types in the embryo. Little is known about the cellular and molecular mechanisms by which Hh acts in the pituitary, or how these signaling systems continue to influence endocrine cell differentiation and proliferation post-embryonically. Our goal is to understand the mechanisms by which Hh induces and functionally patterns the vertebrate pituitary in the embryo and to determine how Hh/Gli signaling influences pituitary growth post- embryonically. In Aim #1 we seek to determine the embryonic origin of the two sub-domains of the adenohypophysis and determine whether Hh/Gli signaling is directly required in placodal cells, a crucial step toward understanding the cellular and molecular mechanisms that induce and pattern the pituitary gland. The goal of Aim #2 is to characterize and quantify endocrine cell proliferation in the larval pituitary and determine how Hh/Gli signaling regulates endocrine cell numbers post-embryonically. These studies are designed to provide insight into how the ordered complexity of this tissue arises, how different endocrine cell types are generated, and how pituitary growth and differentiation are regulated. Answering these questions is important, not least because many diseases have their origins in embryonic development. Errors in Hh signaling at this time, if not corrected, can develop into medical conditions such as holoprosencephaly or endocrine dysfunction, including dwarfism and hypopituitarism. Because Hh inhibitors are being used now to treat several other human tumors, this work may help provide the molecular background needed to bring similar treatments to patients with pituitary adenomas. Comment [MB1]: I assume that stat is in the US? I would insert US here, given that you are applying for PHS money.