PHYSIOLOGY OF STRESS AND CLINICAL APPLICATIONS OF CORTICOTROPIN RELEASING HORMONE

应激生理学和促肾上腺皮质激素释放激素的临床应用

• 批准号: 4693770
• 负责人: G P CHROUSOS
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/4693770
• 关键词: Cushing's syndrome; adrenal disorder; child (0-11); corticotropin releasing factor; dosage; hormone metabolism; hormone regulation /control mechanism; human subject; human tissue; pituitary adrenal axis; pituitary disorders; stress

In this project we seek to advance understanding of the endocrine mechanisms of stress and of the role of corticotropin releasing hormone (CRH) in normal and stress physiology and in disorders of hypothalamic-pituitary-adrenal function. Rapid progress in this area has been made prossible by the recent discovery of the chemical structures of, first, ovine CRH (oCRH) and, more recently, of human CRH (hCRH). Our objectives have been to determine the dose-response relationships for ovine and human CRH in nonhuman primates and in man, to study the metabolic clearance rates of these peptides, to develop methods to measure CRH accurately in tissues and in biological fluids of patients with abnormalities of the hypothalamic-pituitary-adrenal axis, to develop a clinical CRH test, and to evaluate its usefulness in adrenal insufficiency, Cushing's syndrome, and pseudo-Cushing's states. Our studies to date have shown that both ovine and human CRH are active in non-human primates and man. The appropriate dose and mode of testing man have been established and the pharmacological parameters have been determined in both primates and men. CRH stimulation appears to be a useful test in the differential diagnoisis of adrenal insufficiency, Cushing's syndrome and pseudo-Cushing's states. Physiological experiments suggest that Cushing's disease is pituitary, whereas hypercortisolism in depression is hypothalamic in orgin. Succuessful treatment of Cushing's disease with surgery is followed by normalization of the CRH stimulation test. Human CRH causes brief plasma ACTH and cortisol elevations in human subjects that are pulselike and mimic the spontaneously occurring physiologic ACTH and cortisol secretory episodes. This is explained by the brief plasma half-life and the high MCR of this peptide. These properties of hCRH make it an important means for the study of the physiology of the hypothalamic-pituitary-adreanl axis. Administration of hCRH in a pulsatile fashion restores the secretory pattern of cortisol in patients with hypothalamic adrenal insufficiency.

在这个项目中，我们试图增进对内分泌的了解 应激机制及促肾上腺皮质激素释放激素的作用 (CRH)在正常和应激生理学中以及在 下丘脑-垂体-肾上腺功能。这一领域的快速进步已经 最近发现的化学结构使之成为可能， 首先是绵羊CRH(OCRH)，最近是人CRH(HCRH)。我们的 目的是确定绵羊的剂量-反应关系 以及人类CRH在非人灵长类动物和人类体内的代谢 这些多肽的清除率，以建立测定CRH的方法 在患者的组织和生物液中准确 下丘脑-垂体-肾上腺轴的异常，发展为 临床促肾上腺皮质激素释放激素试验，并评估其在肾上腺功能不全中的作用， 库欣综合征和假性库欣状态。到目前为止我们的研究有 研究表明，绵羊和人类CRH在非人类灵长类动物中都很活跃， 天哪。确定了合适的试验剂量和试验方式 已经测定了两种灵长类动物的药理参数 还有男人。促肾上腺皮质激素释放激素刺激似乎是一种有用的鉴别试验。 肾上腺皮质功能不全、库欣综合征和 伪库欣状态。生理实验表明库欣的 疾病是垂体性的，而抑郁症中的皮质醇过多则是 下丘脑在原发部位。治疗库兴氏病的成功经验 手术后CRH刺激试验正常化。人类 CRH导致受试者血浆ACTH和皮质醇短暂升高 是脉冲状的，模仿自发产生的生理性ACTH和 皮质醇分泌性发作。这是由短暂的等离子体解释的 半衰期和该多肽的高MCR。HCRH的这些特性使 它是研究人体生理的重要手段。 下丘脑-垂体-肾上腺轴。人促肾上腺皮质激素释放激素脉冲式给药 时尚恢复慢性阻塞性肺疾病患者皮质醇分泌模式 下丘脑肾上腺功能不全。