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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：
3152467
负责人：
STANLEY ULICK
金额：
$ 11.22万
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 1988-03-31
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.

皮质类固醇的生物合成将在沿着途径的最终激素产品，皮质醇和醛固酮。的将在切割点检查途径的早期部分，通过建立胆固醇侧链缺陷的动物模型，在这一点上，并确定缺乏的机制，侧链裂解活性。还将寻求证据来证实胆固醇侧链碳链酶可逆阻断假说在人类胎儿中自然发生。 21-羟化酶的作用天然盐皮质激素合成不足拮抗剂将被调查，以及缺陷的性质，醛固酮生物合成在这个先天性的错误。在远端的情况下皮质酮和醛固酮之间的醛固酮生物合成缺陷， II型缺陷的成年患者调整的机制，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，以确定类型的存在我的缺陷涉及醛固酮生物合成途径的这一部分。将继续研究11 β-羟基氧化还原酶平衡幼年型低肾素盐皮质激素的变化高血压此外，类固醇模式将在一个这种疾病的生化变体，其中综合征被逆转，地塞米松。研究我们新发现的将进行皮质醇18-氧化酶途径。这个的用处途径在醛固酮瘤的鉴别诊断中的作用，检查双侧肾上腺皮质增生。研究还将对这一途径的优势机制进行了研究，常染色体显性ACTH依赖性醛固酮增多症。确认将还应寻求初步调查结果，即最终产品的皮质醇18-氧化酶途径是17 α-羟基醛固酮。生物后者类固醇的意义及其对临床的贡献将研究它过度产生的疾病的情况。