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）：在大脑开发期间， 类固醇激素可以对生殖生理和 动物的行为。在大脑中异常的类固醇激素作用 发育可能导致广义内分泌疾病，例如肾上腺 增生，不育或早期/早熟青春期；因此，理解 大脑内如何调节类固醇激素的作用至关重要 了解内分泌疾病是如何发生的。核受体共激活因子是 最近确定的与细胞内相互作用的蛋白质类 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对对类固醇的作用的贡献 大脑发育以前尚未探索。当前建议使用 大鼠作为动物模型，重点关注核受体共激活因子 影响发展中大脑中类固醇激素的作用。我们将使用反义 寡脱氧核苷酸以降低特定核受体的表达 大脑发育过程中的共激活因子并调查对 性二态行为和性二态性脑结构。这 项目还将研究核受体共激活因子如何 参与调节两个不同的大脑分化现象： 男性化，定义为增加的男性典型行为，并且 定义为降低女性典型行为。我们有 最近发现特定的核受体共激活因子至关重要 参与类固醇引起的限定，但不参与男性化 脑。我们建议进一步探讨核受体共激活因子如何 影响类固醇引起的大脑的“性别分化”，以及它们如何 调节男性化与大脑的限定。 我的长期职业目标是成为一名独立科学家 学术环境并为生殖领域做出重要贡献 生理。他的职业目标是继续在这里进行的研究 自己的实验室，竞争研究资金，并培训毕业生和 博士后生。