Nuclear Receptor Co-Activators and Brain Sex Differences

描述(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和 动物的行为。大脑中类固醇激素的异常作用 发育可导致全身内分泌紊乱，如肾上腺 增生症、不孕症或性早熟；因此，理解 类固醇激素在大脑中的作用是如何调节的 了解内分泌紊乱是如何发生的。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。这个 核受体共激动子在类固醇激素作用中的作用 以前还没有人研究过大脑发育。目前的提案使用 将大鼠作为动物模型，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 寡核苷酸降低特定核受体表达的实验研究 在大脑发育过程中的协同激活剂，并调查其对 性二态行为和性二态大脑结构。这 该项目还将调查核受体共激活剂可能是如何 参与调节两种截然不同的大脑分化现象： 男性化，定义为男性典型行为的增加，以及 去女权化，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子对 参与类固醇诱导的去女性化，但不参与男性化 大脑。我们建议进一步探索核受体共激活剂是如何 影响类固醇诱导的大脑“性别分化”，以及它们是如何 调节男性化与去女性化的大脑。 我的长期职业目标是在一年内成为一名独立科学家 学术背景和对生殖领域的重要贡献 生理学。他的职业目标是继续在这里介绍的研究 他自己的实验室，竞争研究资金，培养研究生和 博士后。

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.