ANDROGEN METABOLISM IN CHILDHOOD

这是第32个资助年头的修订后的拨款申请。 主要强调的是表型的基因相关性。 结合分子和临床研究。两个单基因缺陷将 被研究：21-羟基酶缺乏，导致疾病 先天性肾上腺皮质增生症(CAR)和11β-HSD2缺乏症 是该病明显的矿物质皮质激素过多(AME)的原因。 我们招募了一名医学信息学专家，他已经建立了 描述CAH患者纵向数据的数据库 紧随其后的是纽特博士30多年。该数据库包括广泛的 357例慢性阻塞性肺疾病患者的临床及分子遗传学研究 将被分析以确定接受治疗的患者的最终结果 使用糖皮质激素。慢性重型肝炎产前治疗的远期疗效观察 用地塞米松对认知和行为进行研究。我们有 在一个门诺派血缘家庭中发现了一种新的轻度AME 并有机会调查其他2000岁的人- 成员群体中11HSDB2基因突变与我们的 有耐心的。我们还将研究矿物皮质激素和 糖皮质激素对体内外胶原蛋白合成的影响 HSD2缺乏症。总括而言，我们建议继续调查 我们新组建的团队由戴维斯博士组成。 新、威尔逊、奥贝德、哈诺斯克-亚伯、纽菲尔德和迈耶-巴尔堡。我们的 最近的进展证明，这个小组有能力推进这项工作 开始于33年前。我们团队的优势是：1)有钱人 转诊至我们科室进行类固醇诊断的患者来源 精神障碍和高血压。2)我们是美国唯一的团体。 常规开展CAR的产前诊断和治疗 积累了大量接受产前治疗的婴儿- 学习。3)由于New博士自1955年以来一直留在Nyh-CMC， 接下来是从出生到成年的类固醇紊乱。很少有一个 一组患者被如此仔细地持续记录下来 临床、激素和分子遗传学数据。4)威尔逊博士带来了 在分子遗传学方面具有特殊的专业知识，与 临床团队。5)Ranauke-Abel博士增加了一个新的维度， 类固醇激素促肝纤维化和抗肝纤维化作用的研究 在病人和培养的人类细胞中。6)和谐互动 分子遗传学家、生物化学家、心理内分泌学家和 在处理病人方面有丰富经验的临床医生。

This is a revised submission of a grant in its 32nd year of funding. The primary emphasis is on the correlation of genotype of phenotype combining molecular and clinical studies. Two monogenic defects will be studied: 21-hydroxylase deficiency, which results in the disease Congenital Adrenal Hyperplasia (CAR), and 11beta-HSD2 deficiency, which is the cause of the disease Apparent Mineralocorticoid Excess (AME). We have recruited a medical informatics specialist who has established a database describing the longitudinal data of patients with CAH followed by Dr. New for over 30 years. The database includes extensive clinical and molecular genetics studies of 357 patients with CAR and will be analyzed to determine the final outcome of patients treated with glucocorticoid. The long term effects of prenatal treatment of CAH with dexamethasone on cognition and behavior will be studied. We have discovered a new mild form of AME in a consanguineous Mennonite family and have an opportunity to investigate whether others in their 2,000- member congregation have mutations in the 11HSDB2 gene similar to our patient. We will also study the effect of mineralocorticoids and glucocorti-coids on collagen synthesis in vivo and in vitro in 11beta- HSD2 deficiency. Overall, we propose to continue the investigation of steroid disorders with our newly constituted team consisting of Drs. New, Wilson, Obeid, Hanauske-Abel, Newfield, and Meyer-Bahlburg. Our recent progress attests that this team is capable of advancing the work started 33 years ago. The strengths of our group are: 1) The rich source of patients referred to our division for diagnosis of steroid disorders and hypertension. 2) We are the only group in the U.S.A. routinely carrying out prenatal diagnosis and treatment of CAR and thus have accumulated a large population of prenatally-treated infants to- study. 3) As Dr. New has remained at NYH-CMC since 1955, patients with steroid disorders from birth to adulthood are followed. Rarely has a group of patients been so carefully documented continuously with clinical, hormonal, and molecular genetics data. 4) Dr. Wilson brings special expertise in molecular genetics and works compatibly with the clinical teams. 5) Dr. Ranauske-Abel adds a new dimension, with the investigation of pro-and antifibrotic effects of steroid hormones in patients and in cultured human cells. 6) The harmonious interaction of molecular geneticists, biochemists, psychoendocrinologists, and clinicians with great experience in dealing with patients.