Corticotropin-Releasing Hormone-Binding Protein

促肾上腺皮质激素释放激素结合蛋白

基本信息

批准号：
6751606
负责人：
AUDREY F. SEASHOLTZ
金额：
$ 25.13万
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：
1990
资助国家：
美国
起止时间：
1990-12-01 至 2006-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6751606
关键词：
corticotropin releasing factor estrogens gene deletion mutation gene expression genetic regulation genetically modified animals glucocorticoids hormone binding protein hormone regulation /control mechanism hypothalamic pituitary adrenal axis laboratory mouse protein localization steroids

项目摘要

DESCRIPTION: (Scanned from the applicant's abstract) Corticotropin-releasing hormone (CRH) is widely recognized as the key physiological regulator of the mammalian stress response. Within the hypothalamic-pituitary-adrenal (HPA) axis, CR1-I is the principal hypothalamic hormone controlling pituitary ACTH synthesis and release. At other sites in the central nervous system (CNS), CRH is thought to act as a neurotransmitter to mediate the behavioral, autonomic, and immunological responses to stress. The recent characterization of urocortin, a new CR1-I-like ligand in mammals, adds to the complexity of the CRH system. Both CRH and urocortin mediate their endocrine and/or synaptic effects via two classes of CRH receptors. Similarly, both CRH and urocortin bind to the CRH-binding protein (CRH-BP). This secreted binding protein is smaller than the CRH receptors, but binds CRH and urocortin with an affinity equal to or greater than that of the receptors, and blocks CRH-mediated ACTH secretion in vitro. The CRH-BP is expressed in the anterior pituitary and brain of rodents and primates. Some regions of CRH-BP expression colocalize with sites of CRH synthesis or release, suggesting that this binding protein may have a profound impact on the biological activity of CRH as a hypothalamic releasing factor and neurotransmitter. We have hypothesized that the CRH-BP is an important modulator of the actions of CRH and other CRH-like ligands in the pituitary and central nervous system in vivo. Recent studies in our laboratory suggest that gonadal steroids regulate pituitary CRH-BP expression. This sexual dimorphism in CRH-BP expression suggests that the CRH-BP may exhibit new gender-specific modulatory roles in the pituitary and brain. Studies in this proposal will examine the modulatory roles of the CRH-BP by characterizing its regulation in vivo and in vitro and examining its functions in mouse models of altered CRH-BP expression, paying particular attention to sexually dimorphic phenotypes. Studies in Aim I examine the in vivo regulation of pituitary CRH-BP expression by gonadal steroids. In Aim II, the molecular mechanisms mediating steroid hormone regulation of CRH-BP gene regulation will be examined, focusing principally on the differential regulation by glucocorticoids and positive regulation by estrogen. In aims 3 and 4, the in vivo roles of CRH-I-BP will be further analyzed using CRH-BP-deficient mice and new transgenic models of targeted, inducible CRH-BP overexpression. As dysregulation of CR1-I activity is thought to play a significant role in major depression, anxiety disorders, and anorexia nervosa, a clearer understanding of the role of CRH-BP in the modulation of activity of CR1-I and other CRH-like ligands may be important to our understanding of the etiology and treatment of these human disease states.

描述：（从申请人的摘要中扫描）促肾上腺皮质激素释放激素（CRH）被广泛认为是机体的关键生理调节因子。哺乳动物的应激反应。在下丘脑-垂体-肾上腺 (HPA) 内轴，CR1-I 是控制垂体 ACTH 的主要下丘脑激素合成和释放。在中枢神经系统 (CNS) 的其他部位，CRH 被认为作为神经递质来调节行为、自主、以及对压力的免疫反应。最近的特征尿皮质素是哺乳动物中一种新的 CR1-I 样配体，增加了 CRH系统。 CRH 和尿皮质素均介导其内分泌和/或突触通过两类 CRH 受体发挥作用。同样，CRH 和尿皮质素与 CRH 结合蛋白 (CRH-BP) 结合。这种分泌性结合蛋白是小于 CRH 受体，但以亲和力结合 CRH 和尿皮质素等于或大于受体的作用，并阻断 CRH 介导的 ACTH 体外分泌。 CRH-BP 在垂体前叶和大脑中表达啮齿动物和灵长类动物。 CRH-BP 表达的某些区域与 CRH 合成或释放位点，表明该结合蛋白可能 CRH作为下丘脑的生物活性具有深远的影响释放因子和神经递质。我们假设 CRH-BP 是 CRH 和其他 CRH 样配体作用的重要调节剂体内垂体和中枢神经系统。我们实验室的最新研究表明性腺类固醇调节垂体 CRH-BP 表达。这种性 CRH-BP 表达的二态性表明 CRH-BP 可能表现出新的垂体和大脑中性别特异性的调节作用。这方面的研究该提案将通过表征其特征来检查 CRH-BP 的调节作用体内和体外调节并检查其在小鼠模型中的功能改变 CRH-BP 表达，特别注意性别二态性表型。 Aim I 中的研究检查垂体 CRH-BP 的体内调节通过性腺类固醇表达。在目标 II 中，介导的分子机制将检查 CRH-BP 基因调节的类固醇激素调节，重点关注主要是糖皮质激素的差异调节和积极的调节雌激素的调节。在目标 3 和 4 中，CRH-I-BP 的体内作用将是使用 CRH-BP 缺陷小鼠和新的转基因模型进行进一步分析靶向、诱导型 CRH-BP 过表达。由于 CR1-I 活性失调被认为在重度抑郁症、焦虑症、和神经性厌食症，更清楚地了解 CRH-BP 在 CR1-I 和其他 CRH 样配体活性的调节可能对我们对这些人类疾病状态的病因和治疗的理解。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mapping of the mouse corticotropin-releasing hormone receptor 2 gene (Crhr2) to chromosome 6.

小鼠促肾上腺皮质激素释放激素受体 2 基因 (Crhr2) 至 6 号染色体的定位。

DOI：
10.1007/s003359900644
发表时间：
1997
期刊：
Mammalian genome : official journal of the International Mammalian Genome Society
影响因子：
0
作者：
Lesh,JS;Burrows,HL;Seasholtz,AF;Camper,SA
通讯作者：
Camper,SA

Transcriptional regulation of corticotropin-releasing hormone-binding protein gene expression in astrocyte cultures.

星形胶质细胞培养物中促肾上腺皮质激素释放激素结合蛋白基因表达的转录调控。