Estrogenic regulation of the hippocampal ubiquitin-proteasome system and its role in memory and structural plastcity

海马泛素-蛋白酶体系统的雌激素调节及其在记忆和结构可塑性中的作用

• 批准号: 10735271
• 负责人: Karyn M Frick
• 金额: $ 51.61万
• 依托单位: UNIVERSITY OF WISCONSIN MILWAUKEE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735271
• 关键词: 26S proteasome; Actins; Address; Adult; Alzheimer' s Disease; Anxiety Disorders; Automobile Driving; Brain; Characteristics; Complex; Data; Dendritic Spines; Development; Dorsal; Estradiol; Estrogen Receptors; Etiology; Female; Functional disorder; Generations; Glutamate Receptor; Goals; Gonadal Steroid Hormones; Hippocampus; Ion Channel; Knowledge; Mass Spectrum Analysis; Measures; Mediating; Memory; Memory impairment; Mental Depression; Mental disorders; Mission; Molecular; Mus; National Institute of Neurological Disorders and Stroke; Nervous System; Neurons; Nuclear; Outcome; Pathway Analysis; Patients; Persons; Pharmacology; Play; Polymers; Polyubiquitination; Proteasome Inhibition; Protein Biosynthesis; Proteins; Proteomics; Public Health; Publishing; Regulation; Report (document); Research; Rodent; Role; Sex Differences; Signal Transduction; Slice; Synapses; Synaptic plasticity; System; Testing; Tissues; Ubiquitin; Vertebral column; Woman; Work; behavioral outcome; calmodulin-dependent protein kinase II; density; effective therapy; estrogenic; hormone regulation; in vivo; innovation; insight; male; memory consolidation; men; multicatalytic endopeptidase complex; nervous system disorder; neuromechanism; neuropsychiatric disorder; neuropsychiatry; novel; novel therapeutics; pharmacologic; polymerization; protein degradation; receptor; sex; ubiquitin mediated proteasome degradation

Project Summary Memory impairment is a defining characteristic of many neuropsychiatric disorders, however, an understanding of the complex neural mechanisms regulating hippocampal memory formation remains elusive. The sex steroid 17β-estradiol (E2) is a powerful modulator of hippocampal plasticity and memory in both males and females, however the neural mechanisms through which this occurs are poorly understood. Therefore, the long-term goal of our research is to pinpoint the neural mechanisms through which E2 regulates hippocampal memory consolidation in males and females. The overall objectives of this application are to determine the mechanisms through which E2 regulates activity of the ubiquitin proteasome system (UPS) and the extent to which proteasomal protein degradation contributes to estrogenic regulation of memory consolidation and hippocampal dendritic spine density in both sexes. Although UPS-mediated protein degradation in the hippocampus is essential for synaptic remodeling and memory consolidation, the role that UPS activity plays in mediating E2’s modulatory effects on memory formation and spine remodeling in either sex remains completely unexplored. Our central hypothesis is that UPS-mediated protein degradation in the DH is triggered by E2 acting at estrogen and glutamate receptors and is a principal mechanism through which E2 promotes memory consolidation and CA1 spine density. This hypothesis is based on previous work suggesting overlapping mechanisms through which E2 and UPS activity contribute to hippocampal plasticity and memory. Our central hypothesis will be evaluated in the following three specific aims: 1) determine the cellular mechanisms through which E2 activates hippocampal UPS activity, 2) identify protein targets of E2-induced UPS activation across subcellular compartments, 3) establish a key role for proteasome activity in E2-induced facilitation of memory consolidation and CA1 spine density. Regionally- and temporally- specific pharmacological manipulations will be used to establish receptor mechanisms underlying E2-UPS interactions in the dorsal hippocampus, as well as the structural and behavioral outcomes of these interactions. Cutting edge ubiquitin-specific mass spectrometry-based proteomics will also be used to identify novel proteins targeted by E2 for degradation. This work is innovative in that it represents a fundamental shift from a conventional focus on protein synthesis as a primary contributor to estrogenic memory modulation to a novel consideration of protein degradation as an equal and opposite counterpart necessary for estrogenic regulation of hippocampal plasticity and memory. This contribution is significant because it will provide essential foundational knowledge about the mechanisms through which E2 regulates memory consolidation in both sexes, which could lead to the development of novel sex-specific treatments to address the memory dysfunction observed in numerous mental disorders.

项目摘要 记忆障碍是许多神经精神疾病的定义特征，然而， 调节海马记忆形成的复杂神经机制仍然是难以捉摸的。性类固醇 17β-雌二醇（E2）是男性和女性海马可塑性和记忆的强有力调节剂， 然而，这种情况发生的神经机制却知之甚少。因此，长期目标 我们的研究重点是确定E2调节海马记忆的神经机制 男性和女性的巩固。本申请的总体目标是确定 通过E2调节泛素蛋白酶体系统（UPS）的活性， 蛋白酶体蛋白降解有助于记忆巩固和海马的雌激素调节 两性树突棘密度。虽然UPS介导的海马体蛋白质降解， 对于突触重塑和记忆巩固至关重要，UPS活性在介导E2 在任何性别中对记忆形成和脊柱重塑的调节作用仍然完全未被探索。我们 中心假设是，在DH中UPS介导的蛋白质降解是由E2作用于雌激素触发的， 谷氨酸受体，是E2促进记忆巩固和CA 1的主要机制 棘密度这一假设是基于以前的工作，提出了重叠的机制，通过E2 和UPS活性有助于海马的可塑性和记忆。我们的中心假设将在 本研究的目的有三：1）明确E2激活海马神经元的细胞机制 UPS活性，2）鉴定E2诱导的UPS跨亚细胞区室激活的蛋白质靶标，3） 确定蛋白酶体活性在E2诱导记忆巩固和CA 1棘易化中的关键作用 密度的区域和时间特异性药理学操作将用于建立受体 背侧海马中E2-UPS相互作用的潜在机制，以及背侧海马的结构和行为 这些互动的结果。尖端的基于泛素特异性质谱的蛋白质组学也将成为 用于鉴定E2靶向降解的新蛋白质。这项工作是创新的，因为它代表了一个 从传统的关注蛋白质合成作为雌激素记忆的主要贡献者的根本转变 调制到一个新的考虑蛋白质降解的平等和相反的对应必要的 海马可塑性和记忆的雌激素调节。这一贡献意义重大，因为它将提供 关于E2调节记忆巩固的机制的基本知识， 这可能会导致开发新的性别特异性治疗方法来解决记忆问题。 在许多精神疾病中观察到的功能障碍。