Regulation of Reproduction

生殖调节

基本信息

批准号：
6897248
负责人：
SYNTHIA H MELLON
金额：
$ 33.19万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-08-01 至 2006-06-30
项目状态：
已结题

项目摘要

The long term objective of this project is a thorough understanding of how steroid hormone synthesis is regulated in a developmental and tissue-specific fashion, and how dysregulation may result in reproductive disorders such as polycystic ovarian syndrome (PCOS). The genes for steroidogenic enzymes are transcriptionally regulated at several levels: developmentally, tissue specifically, and hormonally. This regulation shares common features but also differs among the various genes for the steroidogenic enzymes and among various mammals. We will focus on the gene encoding P450c17 (17alpha hydroxylase/17,2 lyase) as it is the key branch point in steroidogenesis, it has been implicated in the etiology of PCOS, and it may be involved in early development of nervous and reproductive systems. Its expression in the human adrenal is required for the synthesis of 17 hydroxy C21 steroids (e.g. cortisol) and for synthesis of C19 sex steroids in the gonads and brain. In the nervous system, expression of P450c17 also results in DHEA synthesis, a potent neuromodulators. We have been using the rodent as our model system for studying the transcriptional regulation of this gene, and have identified cis-acting DNA elements and several novel trans-acting nuclear factors. One of these transcription factors, SET, had been identified from a chromosomal translocation in a patient with acute undifferentiated leukemia, but its role as a transcription factor way unknown. We shall now determine the mechanism of SET action by identifying its DNA binding, transactivation, and potential dimerization domains, and identifying co-factors that may interact with SET to participate in its transactivating functions. AS SET is abundantly expressed and regulates P450c17 expression in the developing gonad and nervous system, we will determine if these co-factors are tissue- specifically expressed, and/or if they modify other known functions of SET. Our studies localizing cis-active elements in the rat P450c17 gene have identified a region bound by a factor that we call StF-IT-2, that interacts with the orphan nuclear receptor SF-1 in a novel way, to regulate P450c17 transcription. We will characterize that interaction, and purify, characterize and clone the cDNA for StF-IT-2. Successful completion of these studies will give us a better understanding of how the gonadal and nervous systems initiate steroidogenesis, the mechanism of action of a new class of transcription factor, novel mechanisms by which SF-1 regulates gene expression, and will identify another transcription factor that may participate in a unique aspect of P450c17 expression.

该项目的长期目标是对类固醇激素合成如何以发育和组织特异性的方式调节，以及失调可能导致生殖障碍（如多囊卵巢综合征（PCOS））。类固醇生成酶的基因在多个级别进行了转录调节：在发育，组织和荷尔蒙上。该调节具有共同特征，但在各种基因的类固醇生成酶和各种哺乳动物之间也有所不同。我们将重点放在编码P450C17（17Alpha羟化酶/17,2裂解酶）的基因上，因为它是类固醇生成的关键分支点，它与PCOS的病因有关，并且可能与神经和生殖系统的早期发展有关。合成17种羟基C21类固醇（例如皮质醇）和在性腺和大脑中C19性类固醇合成的合成所必需的。在神经系统中，P450C17的表达还导致DHEA合成，这是一种有效的神经调节剂。我们一直在使用啮齿动物作为我们的模型系统来研究该基因的转录调控，并鉴定了顺式作用DNA元素和几种新型的跨作用核因子。这些转录因子之一是从急性未分化白血病的患者中从染色体易位中鉴定出来的，但其作用是转录因子方式未知。现在，我们将通过识别其DNA结合，反式激活和潜在的二聚化域，并识别可能与SET相互作用以参与其反式激活功能的共同因素来确定设定作用的机制。由于集合表达了大量表达，并调节发育中的性腺和神经系统中的P450C17表达，我们将确定这些co因子是否特异性表达，和/或它们是否修改了其他已知功能。我们的研究将大鼠P450C17基因中的顺式活性元件定位在我们称为STF-IT-2的因子的区域中，该区域以新颖的方式与孤儿核受体SF-1相互作用，以调节P450C17转录。我们将表征这种相互作用，并纯化，表征和克隆STF-IT-2的cDNA。这些研究的成功完成将使我们更好地了解性腺和神经系统如何启动类固醇生成，新的转录因子的作用机制，SF-1调节基因表达的新型机制，并将识别可能参与P450C17表达的独特方面的另一种转录因子。

项目成果

期刊论文数量（32）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Biosynthesis of the neurosteroid 3 alpha-hydroxy-4-pregnen-20-one (3 alpha hp), a specific inhibitor of FSH release.

神经类固醇 3 α-羟基-4-孕烯-20-酮 (3 α hp) 的生物合成，一种 FSH 释放的特异性抑制剂。

DOI：
10.1210/endo.142.11.8477
发表时间：
2001
期刊：
Endocrinology.
影响因子：
0
作者：
Griffin,LD;Mellon,SH
通讯作者：
Mellon,SH

DNA sequence-dependent regulation of SF-1-mediated transcription.

SF-1 介导的转录的 DNA 序列依赖性调节。

DOI：
10.1089/dna.2005.24.148
发表时间：
2005
期刊：
DNA and cell biology.
影响因子：
0
作者：
Brake,PaulB;Bair,SusannaR;Mellon,SynthiaH
通讯作者：
Mellon,SynthiaH

Regulation of uterine gamma-aminobutyric acid(A) receptor subunit expression throughout pregnancy.

整个妊娠期间子宫γ-氨基丁酸（A）受体亚基表达的调节。

DOI：
10.1210/endo.142.5.8153
发表时间：
2001
期刊：
Endocrinology.
影响因子：
0
作者：
Fujii,E;Mellon,SH
通讯作者：
Mellon,SH

Role of adrenal renin in the regulation of adrenal steroidogenesis by corticotropin.

肾上腺肾素在促肾上腺皮质激素调节肾上腺类固醇生成中的作用。

DOI：
10.1073/pnas.91.1.148
发表时间：
1994
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Sander,M;Ganten,D;Mellon,SH
通讯作者：
Mellon,SH

Biosynthesis of neurosteroids and regulation of their synthesis.

神经类固醇的生物合成及其合成的调节。