# Identifying mediators of sex hormone uptake and signaling

> **NIH NIH F32** · STANFORD UNIVERSITY · 2022 · $43,866

## Abstract

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.

## Key facts

- **NIH application ID:** 10331844
- **Project number:** 5F32MH125593-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Nicole Yishi Leung
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $43,866
- **Award type:** 5
- **Project period:** 2021-03-16 → 2022-10-03

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10331844

## Citation

> US National Institutes of Health, RePORTER application 10331844, Identifying mediators of sex hormone uptake and signaling (5F32MH125593-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10331844. Licensed CC0.

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