Identifying mediators of sex hormone uptake and signaling

项目摘要/摘要 性激素对大脑和身体的性别分化和不同的生理过程至关重要 在我们的一生中。特别是，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。许多神经科和精神科 病情，包括抑郁和焦虑，创伤后应激障碍，阿尔茨海默病，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的表现与性别比例或结局不甚了解。 理由。这些性别差异可能是由于性二型性分化或功能失调造成的 受性激素影响的神经网络。尽管性激素对健康和 疾病，我们对它们如何影响细胞功能以及性激素通过何种机制 调节神经回路以影响社会行为仍然是有限的。人们普遍认为性激素很小， 在质膜上被动扩散的亲脂性生物活性物质没有被重新讨论过，尽管 越来越多的证据表明，类固醇激素存在促进摄取的机制。此外, 性激素如何通过基因表达的转录调控调节细胞功能 而参与细胞内信号通路的快速非转录机制很差。因此，一个深入的 对性激素作用机制的研究将为了解它们在健康和健康中的作用提供重要的见解 疾病，以及对神经和精神疾病有影响的生物医学应用。 我建议利用最近的技术进步，开发新的工具来识别和功能 描述性激素相互作用的蛋白质，这些蛋白质对性激素的摄取和信号传递很重要。我假设 存在许多未知的组织特异性转运体和受体来介导性激素的作用。在目标1中，我 将采用两种互补的、不偏不倚的方法来发现便利运输的新媒介和 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 化学反应。在目标2中，我将通过描述目标1中确定的候选交互合作伙伴的特征 性激素反应组织中的表达及其在靶细胞中的功能分析，重点是神经 控制老鼠社会行为的网络。全面了解性激素摄取和 信号将为这些古老的生物活性分子的基础生物学提供新的线索。而且，我的 拟议的工作有可能发现跨领域障碍的新治疗靶点 内分泌学、生育学、癌症、神经学和精神病学。

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.