Identifying mediators of sex hormone uptake and signaling

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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.