Mechanisms of Adrenal Differentiation

肾上腺分化的机制

基本信息

批准号：
6730938
负责人：
GARY D. HAMMER
金额：
$ 32.51万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-02-01 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6730938
关键词：
SDS polyacrylamide gel electrophoresis adrenal glands adrenocorticotropic hormone cell differentiation genetic regulation genetically modified animals hormone regulation /control mechanism laboratory mouse liquid chromatography mass spectrometry nuclear receptors phosphoproteins phosphorylation point mutation protein protein interaction transcription factor two dimensional gel electrophoresis

项目摘要

DESCRIPTION (provided by applicant): The long-range objective of our laboratory is to understand the biochemical mechanisms by which cell-type specific transcription factors direct the differentiation of adrenocortical cells within the adrenal gland. Our strategy for this proposal is to focus on transcriptional regulation mediated by the orphan nuclear receptor, steroidogenic factor-1 (SF-1), a transcription factor that is required for the differentiation of the adrenal cortex. Targeted disruption of the gene encoding SF-1 (Ftzf1, Nr5a1) leads to mouse embryos that lack adrenal glands while point mutations that affect the ability of SF-1 to associate with nuclear receptor coregulators, bind DNA and ultimately activate target genes, result in adrenal insufficiency in humans. Based on our preliminary data, we hypothesize that SF-1 mediated transcriptional activation is specifically regulated by adrenocorticotropin hormone (ACTH) and involves intramolecular modifications and intermolecular protein interactions that serve to modulate transcriptional activation to ultimately control adrenal cell differentiation. Our specific aims are therefore directed towards a systematic analysis of the modification of the SF-1 transcriptional complex by ACTH. We propose to determine the major nuclear phosphoprotein targets of ACTH together with a characterization of the signaling cascades responsible for phosphorylation of components of the complex (specific aim 1), how these modifications regulate the organization of the SF-1 transcription complex (specific aim 2) and the contribution of specific phosphoprotein components of the complex to ACTH-dependent target gene activation in the adrenocortical cell (specific aim 3). We believe that the studies proposed here will provide the framework for understanding the molecular events that dictate adrenocortical cell differentiation.

描述（由申请人提供）：我们实验室的远距离目标是了解细胞类型特异性转录因子指导肾上腺内肾上腺皮质细胞的分化的生化机制。我们对该建议的策略是专注于由孤儿核受体类固醇生成因子1（SF-1）介导的转录调节，这是肾上腺皮质分化所需的转录因子。针对编码SF-1（FTZF1，NR5A1）的基因的靶向破坏会导致缺乏肾上腺的小鼠胚胎，而点突变会影响SF-1与核受体核心控制剂相关的能力，结合DNA并最终激活靶基因，从而导致人类人类的肾上腺不足。根据我们的初步数据，我们假设SF-1介导的转录激活受adn肾上腺皮质激素激素（ACTH）的特异性调节，并且涉及分子内修饰和分子间蛋白质相互作用，这些相互作用可用于调节转录激活，以最终控制肾上腺细胞分化。因此，我们的具体目的是针对ACTH对SF-1转录复合物修饰的系统分析。我们建议确定ACTH的主要核磷蛋白靶标，以及负责复合物组成部分磷酸化的信号传导级联反应（特定目标1），这些修饰如何调节SF-1转录复合物的组织（特定目标2）的组织（特定目标2）以及对Acth依赖于Acth依赖于Acth的特定目标的特定磷酸蛋白组成部分的贡献3. Acth依赖于Acth依赖于Acth依赖于Acth依赖于Acth依赖于Acth依赖于Acth依赖于Acth依赖于Acth依赖于Acth依赖于Acth依赖于Acth依赖于Acth依赖于Acth依赖于Acth依赖于Acth依赖于Acth依赖于Acth conferent confertion。我们认为，这里提出的研究将为理解决定肾上腺皮质分化的分子事件提供一个框架。