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: 6528463
• 负责人: ANTHONY P AUGER
• 金额: $ 0.93万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 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 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6528463
• 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）：在大脑发育期间， 类固醇激素可对生殖生理产生持久影响， 动物的行为。脑内异常类固醇激素作用 发展可能导致全身性内分泌失调，如肾上腺 增生、不孕或性早熟;因此，了解 类固醇激素在大脑中的作用是如何调节的， 了解内分泌失调是如何发生的核受体辅激活剂是 最近发现的一类蛋白质， 类固醇受体并深刻地改变其转录活性。的 核受体辅激活剂对类固醇激素作用的贡献 大脑发育以前没有被探索过。目前的提案使用 以大鼠为动物模型，重点研究核受体共激活物 影响大脑发育中类固醇激素的作用。我们将使用反义 减少特定核受体表达的寡脱氧核苷酸 在大脑发育过程中的共同激活剂，并调查其后果， 两性异形行为和两性异形大脑结构。这 该项目还将研究核受体共激活剂如何可能是 参与调节两种不同的大脑分化现象： 男性化，定义为增加男性典型行为， 非女性化是指女性典型行为的减少。我们有 最近发现，特定的核受体辅激活剂是至关重要的 参与类固醇诱导的女性化，但不参与男性化， 个脑袋我们建议进一步探索核受体辅激活剂 影响类固醇诱导的大脑“性别分化”，以及它们如何影响大脑的性别分化。 调节大脑的男性化和女性化。 我的长期职业目标是成为一名独立的科学家， 学术设置和生殖领域作出重要贡献 physiology.他的职业目标是继续进行这里提出的研究， 他自己的实验室，竞争研究经费，并培养研究生和 博士后研究生。