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CORTICOSTEROID BIOGENESIS, METABOLISM, & MODE OF ACTION

皮质类固醇生物发生、代谢、

基本信息

批准号：
3230696
负责人：
STANLEY ULICK
金额：
$ 11.96万
依托单位：
MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
依托单位国家：
美国
项目类别：
财政年份：
1983
资助国家：
美国
起止时间：
1983-04-01 至 1989-03-31
项目状态：
已结题

项目摘要

Corticosteroid biogenesis will be examined at several points along the pathway to the final hormonal products, cortisol and aldosterone. the early portion of the pathway will be examined at the point of cleavage of the side-chain of cholesterol by establishing an animal model of the defect at this locus and the determination of the mechanism of deficiency of side-chain cleavage activity. Evidence will also be sought to confirm the hypothesis that a reversible block in cholesterol side-chain desmolase occurs naturally in the human fetus. The consequences of 21-hydroxylase deficiency on the synthesis of naturally occurring mineralocorticoid antagonist will be investigated as well as the nature of the defect in aldosterone biosynthesis in this inborn error. In the case of the distal aldosterone biosynthetic defect between corticosterone and aldosterone, the mechanism by which adult patients with the Type II defect adjusts to aldosterone deficiency will be examined. The steroid pattern will also be examined in another group of patients to establish the existence of a Type I defect involving this portion of the aldosterone biosynthetic pathway. Studies will continue on the 11 Beta-hydroxyoxidoreductase equilibrium shift observed in a juvenile form of low-renin mineralocorticoid hypertension. In addition, the steroid pattern will be examined in a biochemical variant of this disorder in which the syndrome is reversed by dexamethasone. Studies on the significance of our newly discovered cortisol 18-oxidase pathway will be conducted. The usefulness of this pathway in the differential diagnosis of aldosteronoma compared to bilateral adrenocortical hyperplasia will be examined. Studies will also be carried out on the mechanism of the predominance of this pathway in autosomaldominant ACTH-dependent hyperaldosteronism. Confirmation will also be sought for the preliminary finding that the final product of the cortisol 18-oxidase pathway is 17Alpha-hydroxyaldosterone. The biological significance of the latter steroid and its contribution to the clinical picture of the disorders in which it is overproduced will be studied.

皮质类固醇的生物发生将在沿线的几个点进行检查通向最终激素产物皮质醇和醛固酮的途径。这个途径的早期部分将在裂解点进行检查建立胆固醇侧链缺陷的动物模型在这一点上，并确定了虚证的机制侧链裂解活性。还将寻找证据以证实假设胆固醇侧链脱氢酶中的可逆阻滞物在人类胎儿中自然发生。21-羟基酶的后果天然合成的矿质皮质激素缺乏将对拮抗者以及缺陷的性质进行调查在这个先天的错误中，醛固酮的生物合成。在远端情况下皮质酮和醛固酮之间的醛固酮生物合成缺陷，成人II型缺陷患者适应机制的研究将检查醛固酮缺乏症。类固醇模式也将是在另一组患者中进行检查以确定一种类型的存在 I缺陷涉及到醛固酮生物合成途径的这一部分。关于11β-羟氧化还原酶平衡的研究将继续进行低肾素盐皮质激素幼年型的移位观察高血压。此外，类固醇模式将在一项这种病症的生化变种，这种病症可通过地塞米松。关于我们新发现的生物多样性的意义将进行皮质醇18-氧化酶途径。这样做的用处路径在醛固酮瘤鉴别诊断中的比较检查双侧肾上腺皮质增生症。研究还将对这一途径优势的机制进行了探讨。常染色体显性ACTH依赖的醛固酮增多症。确认将还寻求初步调查结果，即最终产品皮质醇18-氧化酶途径是17Alpha-羟基醛固酮。生物学的后者的意义及其在临床上的贡献将研究过度生产的疾病的图景。