Identifying mediators of sex hormone uptake and signaling

识别性激素摄取和信号转导的介质

• 批准号: 10331844
• 负责人: Nicole Yishi Leung
• 金额: $ 4.39万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-16 至 2022-10-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331844
• 关键词: Address; Affect; Affinity; Aggressive behavior; Alkynes; Alzheimer' s Disease; Anxiety; Area; Attention deficit hyperactivity disorder; Behavioral; Biological Process; Biology; Biotin; Brain; Brain region; Breast; CRISPR screen; CRISPR/Cas technology; Cell Line; Cell membrane; Cell physiology; Cells; Chemistry; Collaborations; Consensus; Detection; Diazomethane; Diffuse; Disease; Endocrinology; Ensure; Estradiol; Female; Fertility; Functional disorder; GPER gene; Gender Identity; Gene Expression; Gene Expression Regulation; Gene Targeting; Genetic Screening; Gonadal Steroid Hormones; Health; Hormone Responsive; Hormones; In Situ Hybridization; In Vitro; Integral Membrane Protein; Investigation; Knowledge; LDL-Receptor Related Protein 2; Libido; Ligation; Light; Longevity; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Membrane Proteins; Mental Depression; Methods; Molecular; Mood Disorders; Moods; Multiple Sclerosis; Mus; Nature; Neurobiology; Neurologic; Neurology; Neurophysiology - biologic function; Nuclear; Outcome; Parkinson Disease; Partner in relationship; Pathway interactions; Perinatal; Pharmacology; Physiological Processes; Post-Traumatic Stress Disorders; Prevalence; Prostate; Proteins; Proteome; Psychiatry; Reporter; Research; Response Elements; Role; Schizophrenia; Sex Differences; Sex Differentiation; Sex Orientation; Sexual Partners; Signal Pathway; Signal Transduction; Social Behavior; Social Controls; Spatial Distribution; Specificity; Techniques; Technology; Testing; Testosterone; Tissues; Transcriptional Regulation; Transgenic Mice; Well in self; Work; autism spectrum disorder; base; chemoproteomics; cognitive function; conditional knockout; crosslink; deep sequencing; health difference; hormonal signals; in silico; in vivo; insight; interest; lipophilicity; male; mimetics; neural circuit; neural network; new therapeutic target; non-genomic; novel; receptor; relating to nervous system; sex; sexual dimorphism; steroid hormone; tool; uptake

Project Summary/Abstract Sex hormones are critical for sexual differentiation of the brain and body and diverse physiological processes across our lifespan. In particular, sex hormone signaling in the brain has been implicated in mood and emotional well-being, cognitive function, sexual orientation, gender identity, and libido. Many neurological and psychiatric conditions, including depression and anxiety, PTSD, Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, ADHD, schizophrenia, and autism manifest with sex-skewed ratios or outcomes for poorly understood reasons. These sex differences may result from dysregulated sexually dimorphic differentiation or function of neural networks influenced by sex hormones. Despite the central importance of sex hormones in health and disease, our understanding of how they influence cellular functions and the mechanisms by which sex hormones modulate neural circuits to affect social behaviors remains limited. The consensus that sex hormones are small, lipophilic bioactive agents that diffuse passively across plasma membranes has not been revisited in spite of mounting evidence indicating the existence of facilitated uptake mechanisms for steroid hormones. In addition, our knowledge of how sex hormones govern cellular functions via transcriptional regulation of gene expression and rapid non-transcriptional mechanisms that engage intracellular signaling pathways is poor. Thus, an in-depth investigation of mechanisms for sex hormone action will provide significant insights into their roles in health and disease, and impactful biomedical applications for neurological and psychiatric conditions. I propose to take advantage of recent technological advances and develop new tools to identify and functionally characterize sex hormone-interacting proteins important for sex hormone uptake and signaling. I hypothesize that many unknown tissue-specific transporters and receptors exist to mediate sex hormone action. In Aim 1, I will employ two complementary, unbiased approaches to discover novel mediators of facilitated transport and intracellular signaling: a CRISPR/Cas9-based genetic screen and a chemoproteomic approach using click chemistry. In Aim 2, I will characterize candidate interacting partners identified in Aim 1 by profiling their expression in sex hormone-responsive tissues and analyzing their function in target cells, with a focus on neural networks that control social behaviors in mice. A comprehensive understanding of sex hormone uptake and signaling will shed new light on the fundamental biology of these ancient bioactive molecules. Moreover, my proposed work has the potential to discover new therapeutic targets for disorders across the fields of endocrinology, fertility, cancer, neurology, and psychiatry.

项目摘要/摘要 性激素对于大脑和身体的性别差异和多样化的身体过程至关重要 在我们的一生中。特别是，心情和情感上隐含了大脑中的性激素信号 幸福感，认知功能，性取向，性别认同和性欲。许多神经和精神病学 疾病，包括抑郁和动画，PTSD，阿尔茨海默氏病，多发性硬化症，帕金森氏症 疾病，多动症，精神分裂症和自闭症以性别扭曲的比率或结果表现出来 原因。这些性别差异可能是由于性二态分化或功能失调而导致的 神经网络受性激素影响。尽管性激素在健康方面具有至关重要的重要性 疾病，我们对它们如何影响细胞功能的理解以及性恐怖的机制 调节神经元电路影响社会行为仍然有限。性激素很小的共识， 尚未重新审视跨质膜的亲脂性生物活性剂 越来越多的证据表明存在制备的类固醇激素摄取机制。此外， 我们对性骑士如何通过基因表达的转录调控来控制细胞功能的知识 并且快速接触细胞内信号通路的非转录机制很差。那是深入的 对性激素作用机制的调查将为他们在健康中的作用和 疾病，以及在神经和精神病疾病中有影响力的生物医学应用。 我建议利用最近的技术进步，并开发新工具来识别和在功能上 表征性爱骑术相互作用的蛋白质对性骑马摄取和信号很重要的蛋白质。我假设 存在许多未知的组织特异性转运蛋白和接收器来介导性激素作用。在AIM 1中，我 将采用两种完整的，公正的方法来发现准备好的运输的新型调解人和 细胞内信号传导：基于CRISPR/CAS9的遗传筛选和使用Click的化学蛋白质组学方法 化学。在AIM 2中，我将通过分析AIM 1中确定的候选人互动伙伴来表征他们 在性马对响应组织中表达并分析其在靶细胞中的功能，重点是神经 控制小鼠社会行为的网络。对性激素摄取的全面了解和 信号传导将为这些古老的生物活性分子的基本生物学提供新的启示。而且，我的 拟议的工作有可能发现整个领域疾病的新治疗靶点 内分泌，生育能力，癌症，神经病学和精神病学。