Men1 Control of Endocrine Cell Growth and Differentiation

描述（由申请人提供）：内分泌组织的受控生长对健康至关重要，但对支配内分泌细胞生长和分化的内在细胞调节因子知之甚少。Men 1基因的突变促进了1型多发性内分泌瘤（MEN 1）的发病机制，最近的研究表明，Men 1基因的蛋白产物menin是内分泌细胞增殖和命运的关键调节因子。Menin与其他核蛋白和染色质结合，促进特异性共价组蛋白修饰，从而激活或抑制靶基因表达。确定menin的目标，menin在基因调控中的功能，以及与menin相互作用的信号通路，应该揭示内分泌生长控制和肿瘤抑制的关键机制。本实验的目的是阐明menin在内分泌细胞生长和肿瘤形成中的分子和体内功能。小鼠Men 1失活重现了人类MEN 1综合征的一些但不是全部特征，表明Men 1突变伴随着其他未识别的变化，以促进内分泌肿瘤的发病机制。在其他情况下，如怀孕和肥胖，胰岛等内分泌细胞的生长是为了满足宿主生理需求的变化，我们的研究表明，menin控制着这种适应性增殖。Menin与编码生长调节因子（如c-Myc）的基因相关，并抑制其在胰腺内分泌细胞中的表达，但抑制机制尚不清楚。本申请中的实验将测试menin控制染色质修饰以确保内分泌胰腺中c-Myc的正常水平和活性的假设。该提案的具体目标是：（1）使用新的条件遗传学方法来破坏Me/77缺陷小鼠中的TGF-β信号传导，以测试TGF-β通路是否与体内menin合作来控制内分泌肿瘤中的基因表达、生长和肿瘤进展。(2)确定抑制候选靶基因（如c-Myc）表达的染色质修饰的menin依赖性机制。(3)确定menin调节适应性胰岛细胞生长的机制。这里提出的menin的分析将大大增加我们对内分泌细胞生长控制和肿瘤抑制的理解。因此，这些研究可能会导致新的诊断，预后，或治疗策略的广泛的人类疾病源于失调的内分泌细胞生长，包括糖尿病和内分泌肿瘤的子集。

DESCRIPTION (provided by applicant): Controlled growth of endocrine tissues is essential for health, but little is known about the intrinsic cellular regulators that govern endocrine cell growth and differentiation. Mutations of the Men1 gene promote pathogenesis of type 1 multiple endocrine neoplasia (MEN1), and recent studies suggest that menin, the protein product of the Men1 gene, is a key regulator of endocrine cell proliferation and fates. Menin associates with other nuclear proteins and chromatin to promote specific covalent histone modifications that can activate or repress target gene expression. Identification of menin targets, menin functions in gene regulation, and signaling pathways that interact with menin should reveal crucial mechanisms in endocrine growth control and tumor suppression. The goal of experiments in this proposal is to elucidate the molecular and in vivo functions of menin in endocrine cell growth and neoplasia. Men1 inactivation in mice recapitulates some, but not all features of human MEN1 syndrome, indicating that additional unidentified changes accompany Men1 mutation to promote pathogenesis of endocrine neoplasias. In other conditions like pregnancy and obesity endocrine cells like pancreatic islets facultatively grow to meet changes in host physiologic needs, and our studies suggest that menin controls this adaptive proliferation. Menin associates with genes encoding growth regulators like c-Myc and represses their expression in pancreatic endocrine cells, but the mechanisms of repression are unknown. Experiments in this application will test the hypothesis that menin governs chromatin modifications to ensure normal levels and activity of c-Myc in the endocrine pancreas. This proposal's specific aims are to: (1) Use novel conditional-genetic methods to disrupt TGF-beta signaling in Me/77-deficient mice to test if TGF-beta pathways collaborate with menin in vivo to control gene expression, growth, and neoplastic progression in endocrine tumors. (2) Identify menin-dependent mechanisms of chromatin modification that repress expression of candidate target genes like c-Myc. (3) Identify mechanisms of menin-regulated adaptive islet cell growth. The analyses of menin proposed here will add substantially to our understanding of endocrine cell growth control and tumor suppression. Thus, these studies may lead to new diagnostic, prognostic, or therapeutic strategies for a broad range of human disorders stemming from dysregulated endocrine cell growth, including subsets of diabetes mellitus and endocrine neoplasias.