Identifying mediators of sex hormone uptake and signaling

识别性激素摄取和信号转导的介质

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要/摘要性激素对于大脑和身体的性别分化以及多种生理过程至关重要特别是，在我们的一生中，大脑中的性激素信号与情绪和情绪有关。幸福感、认知功能、性取向、性别认同和性欲许多神经和精神方面的问题。疾病，包括抑郁症和焦虑症、创伤后应激障碍、阿尔茨海默病、多发性硬化症、帕金森病疾病、注意力缺陷多动症、精神分裂症和自闭症表现出性别比例的偏差或人们对其知之甚少的结果这些性别差异可能是由于两性分化或功能失调造成的。尽管性激素对健康和健康至关重要，但神经网络仍受性激素的影响。疾病，我们对它们如何影响细胞功能以及性激素的机制的理解调节神经回路影响社会行为的共识仍然有限，尽管存在，但被动扩散穿过质膜的亲脂性生物活性剂尚未被重新研究。越来越多的证据表明存在类固醇激素的促进摄取机制。我们对性激素如何通过基因表达的转录调控来控制细胞功能的了解因此，涉及细胞内信号通路的快速非转录机制还很缺乏。对性激素作用机制的研究将为了解其在健康和健康方面的作用提供重要的见解。疾病，以及针对神经和精神疾病的有影响力的生物医学应用。我建议利用最新的技术进步并开发新的工具来识别和功能化描述对性激素摄取和信号转导重要的性激素相互作用蛋白的特征。在目标 1 中，存在许多未知的组织特异性转运蛋白和受体来介导性激素作用。将采用两种互补的、公正的方法来发现便利交通和细胞内信号转导：基于 CRISPR/Cas9 的遗传筛选和使用 click 的化学蛋白质组学方法在目标 2 中，我将通过分析目标 1 中确定的相互作用的候选伙伴来描述他们的特征。性激素反应组织中的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全面了解性激素的摄取和控制。信号传导将为这些古老生物活性分子的基础生物学提供新的线索。拟议的工作有可能发现跨领域疾病的新治疗靶点内分泌学、生育力、癌症、神经病学和精神病学。