Corticotropin-Releasing Hormone-Binding Protein

描述：(摘自申请者摘要)促肾上腺皮质激素释放 激素(CRH)被广泛认为是高血压的关键生理调节因子。 哺乳动物应激反应。在下丘脑-垂体-肾上腺(HPA)内 AXIS，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 被认为是一种神经递质，调节行为，自主神经， 以及对压力的免疫反应。最新的特征描述 Urocortin是哺乳动物中一种新的CR1-I样配体，增加了 CRH系统。促肾上腺皮质激素释放激素和尿皮质激素调节其内分泌和/或突触 通过两类CRH受体发挥作用。类似地，CRH和尿皮质激素 结合CRH结合蛋白(CRH-BP)。这种分泌的结合蛋白是 比CRH受体小，但以亲和力结合CRH和Urocortin 等于或大于受体的受体，并阻断CRH介导的ACTH 体外分泌。CRH-BP在垂体前叶和脑中表达 啮齿动物和灵长类动物。CRH-BP表达的某些区域与 CRH合成或释放的位点，提示该结合蛋白可能 对CRH作为下丘脑的生物活性有深远的影响 释放因子和神经递质。我们假设CRH-BP是 CRH和其他CRH类配体在体内作用的重要调节剂 活体内的垂体和中枢神经系统。我们实验室的最新研究 提示性腺激素对垂体CRH-BP的表达有调节作用。这是性爱 CRH-BP表达的二型性提示CRH-BP可能表现出新的 不同性别在脑下垂体和大脑中的调节作用。在这方面的研究 提案将研究CRH-BP的调节作用，通过表征其 体内外调节及其在小鼠模型中的作用 CRH-BP表达改变，特别注意性二型 表型。AIM研究I：垂体CRH-BP的体内调节 性腺类固醇激素的表达。在AIM II中，调节分子机制 类固醇激素调节CRH-BP基因的调节将被研究，重点 主要是糖皮质激素和正性激素的差异性调节 雌激素的调节作用。在AIMS 3和4中，CRH-I-BP的体内作用将是 利用CRH-BP缺陷小鼠和新的转基因模型进行进一步分析 靶向、可诱导的CRH-BP过表达。作为CR1-I活性的失调 被认为在严重的抑郁症、焦虑症、 和神经性厌食症，更清楚地了解CRH-BP在 调节CR1-I和其他CRH样配体的活性可能对 我们对这些人类疾病的病因和治疗状态的理解。

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.