# NIH grant: Molecular Investigation of the Sperm-Immune Synapse (1R01HD121569-01) — retained record

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[original source ↗](https://reporter.nih.gov/project-details/1R01HD121569-01)

## retained text



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NIH grant 1R01HD121569-01: Molecular Investigation of the Sperm-Immune Synapse
Institute: {'code': 'HD', 'abbreviation': 'NICHD', 'name': 'Eunice Kennedy Shriver National Institute of Child Health and Human Development', 'admin_org_id': '12500030', 'admin_funding_url': ''}. PI: Shaogeng  Tang. Award: $543572.
Start: 2026-08-15T00:00:00.
Fertilization requires successful sperm transit through the female reproductive tract, where resident
macrophages selectively eliminate compromised sperm while permitting viable sperm to reach the egg.
Despite the critical importance of this quality control mechanism for human fertility, the molecular basis for
selective sperm–immune recognition remains unknown. In the United States, 9% of men and 11% of women
experience fertility problems, with immuno-infertility representing a significant contributing factor. This research
addresses a fundamental gap in reproductive biology by investigating the first identified molecular mechanism
for sperm-macrophage recognition. Recent discoveries reveal that human IZUMO1, a sperm acrosomal
membrane protein essential for fertilization, serves as a natural ligand for an orphan receptor on macrophages.
IZUMO1 becomes surface-exposed only after acrosome reaction or when sperm are compromised, making it
an ideal recognition signal for immune clearance. This IZUMO1–macrophage interaction represents the first
identified “sperm–immune synapse” and provides a molecular framework for understanding how macrophages
distinguish between viable and damaged sperm. The research will pursue three specific aims using
complementary biochemical, cellular, and immunological approaches. Aim 1 will decode the molecular
architecture of the sperm–immune synapse by determining high-resolution structures of the IZUMO1-
macrophage receptor complex using high-resolution structural biology approaches, coupled with mutagenesis
studies to map sequence–function relationships at single amino acid resolution. Aim 2 will visualize receptor-
mediated sperm phagocytosis to capture ultrastructural details of sperm–macrophage interactions from
adhesion through internalization. Aim 3 will profile the human antibody repertoire against IZUMO1 by isolating
IZUMO1-reactive B cells from healthy women and performing single-cell sequencing to understand how natural
exposure to sperm antigens could lead to immuno-infertility. This research will establish the first mechanism for
selective macrophage-mediated sperm clearance, providing molecular insights into reproductive immunology
with direct clinical relevance for understanding immuno-infertility. The findings will inform precision diagnostic
approaches for fertility disorders and ultimately advance reproductive health care.
```



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