# Functional analysis of novel testis-expressed secreted and transmembrane proteins

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $509,232

## Abstract

PROJECT SUMMARY
Rather than the traditional approach of studying the function of one gene in a proposal, our team’s discovery-
based approaches have allowed us to define the functions of many novel genes simultaneously. Our
bioinformatic discovery of novel reproductive tract-enriched genes and definition of their functions in mouse
models provide powerful means to place these gene products into unique biological pathways and gain insight
into the molecular processes of mammalian spermatogenesis. With the support of this R01 grant, we created
knockouts of over 150 novel genes using CRISPR/Cas9-mediated genome engineering. We prioritized 27
genes that encode secreted, glycosylphosphatidylinositol (GPI)-anchored, and transmembrane proteins that
are potential contraceptive targets and/or act in spermiogenesis or for sperm maturation or function; knockouts
of 17 of these 27 genes resulted in fertility defects. These classes of genes were chosen because of their
potential relevance to infertility in men and their likelihood as targets for male contraception; ~70% of FDA-
approved drugs target either membrane-bound or secreted proteins, and thus these proteins could be targets
for antibody-based or small molecule contraceptives. To date, these R01 studies have resulted in 38 papers,
including 9 papers in Science, PNAS, and PLoS Genetics. In this R01 grant renewal proposal, we will continue
to utilize our combined expertise in informatics, biochemistry, molecular biology, chemical biology, and
manipulation of the mouse genome. The overall goals of this grant renewal are to mechanistically define the in
vivo functions of six novel male reproductive tract-essential proteins that are required for sperm transit through
the uterotubal junction (UTJ) and to use DNA-Encoded Chemistry Technology (DEC-Tec) to find chemical
entities that can serve as non-hormonal contraceptives. Our hypothesis is that these novel reproductive tract-
specific proteins act in evolutionarily conserved pathways required for sperm function, processes that are
vulnerable to targeting strategies for contraception. Using DEC-Tec, we have already screened multi-billion
compound libraries with contraceptive target proteins in this proposal and identified hits with excellent
structure-enrichment relationships (both predicted specific and pan-inhibitor molecules). Our hypothesis will be
tested in the following Specific Aims: 1) Define the molecular mechanisms of action of five testis-specific
proteins in sperm transit through the UTJ; 2) Determine the functions and functional domains of an epididymis-
specific gene in sperm epididymal maturation and transit through the UTJ; and 3) Use small molecules
identified through DEC-Tec screens to block sperm transit through the UTJ. Our proof-of-principle studies have
important translational implications for human reproductive genetics and contraceptive development: these
essential sperm UTJ transit proteins and interacting pathway proteins are potent...

## Key facts

- **NIH application ID:** 10378949
- **Project number:** 2R01HD088412-06A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** MARTIN M. MATZUK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $509,232
- **Award type:** 2
- **Project period:** 2016-08-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10378949

## Citation

> US National Institutes of Health, RePORTER application 10378949, Functional analysis of novel testis-expressed secreted and transmembrane proteins (2R01HD088412-06A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10378949. Licensed CC0.

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