Nuclear Receptor Co-Activators and Brain Sex Differences

核受体共激活剂和大脑性别差异

• 批准号: 6652458
• 负责人: ANTHONY P AUGER
• 金额: $ 16.63万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-10 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6652458
• 关键词: developmental neurobiology; endocrine disorder; gender difference; hormone regulation /control mechanism; immunocytochemistry; immunofluorescence technique; in situ hybridization; laboratory rat; neuroendocrine system; nuclear receptors; oligonucleotides; receptor expression; steroid hormone; transcription factor; western blottings

DESCRIPTION (provided by applicant): During brain development, the actions of steroid hormones can have lasting effects on reproductive physiology and behavior in animals. Abnormal steroid hormone action in the brain during development can result in generalized endocrine disorders, such as adrenal hyperplasia, infertility, or early/precocious puberty; therefore, understanding how steroid hormone action is regulated within the brain is critical in understanding how endocrine disorders occur. Nuclear receptor co-activators are a recently identified class of proteins that interact with intracellular steroid receptors and profoundly alter their transcriptional activity. The contribution of nuclear receptor co-activators to steroid hormone action on brain development has not been previously explored. The current proposal uses the rat as an animal model and focuses on how nuclear receptor co-activators influence steroid hormone action in the developing brain. We will use antisense oligodeoxynucleotides to reduce the expression of particular nuclear receptor co-activators during brain development and investigate the consequences on sexually dimorphic behaviors and on sexually dimorphic brain structures. This project will also investigate how nuclear receptor co-activators may be involved in regulating two distinct phenomena of brain differentiation: masculinization, which is defined as increased male typical behaviors, and defeminization, which is defined as reduced female typical behaviors. We have recently found that particular nuclear receptor co-activators are critically involved in steroid-induced defeminization but not masculinization of the brain. We propose to further explore how nuclear receptor co-activators influence steroid-induced "sexual differentiation" of the brain, and how they regulate masculinization vs. defeminization of the brain. My long-term career objective is to become an independent scientist within an academic setting and make important contributions to the field of reproductive physiology. It is his career goal to continue the research presented here in a laboratory of his own, compete for research funding, and to train graduate and postdoctoral students.

描述（由申请人提供）：在大脑发育过程中， 类固醇激素可以对生殖生理产生持久影响 动物的行为。大脑中类固醇激素的异常作用 发育可能导致全身内分泌紊乱，例如肾上腺 增生、不孕或性早熟；因此，理解 大脑内类固醇激素作用的调节方式至关重要 了解内分泌失调是如何发生的。核受体共激活剂是 最近发现的一类与细胞内相互作用的蛋白质 类固醇受体并深刻改变其转录活性。这 核受体共激活剂对类固醇激素作用的贡献 此前尚未探索过大脑发育。目前的提案使用 以大鼠作为动物模型，重点研究核受体共激活剂如何 影响发育中的大脑中类固醇激素的作用。我们将使用反义 寡脱氧核苷酸减少特定核受体的表达 大脑发育过程中的共激活剂并研究其后果 性二态性行为和性二态性大脑结构。这 项目还将研究核受体共激活剂如何 参与调节大脑分化的两种不同现象： 男性化，定义为男性典型行为的增加，以及 去女性化，被定义为女性典型行为的减少。我们有 最近发现特定的核受体共激活剂至关重要 参与类固醇诱导的去女性化，但不参与男性化 脑。我们建议进一步探索核受体共激活剂如何 影响类固醇诱导的大脑“性别分化”，以及它们如何 调节大脑的男性化与非女性化。 我的长期职业目标是成为一名独立科学家 学术背景并在生殖领域做出重要贡献 生理。他的职业目标是继续此处介绍的研究 自己的实验室，竞争研究经费，培养研究生和 博士后学生。