# Developmental Mechanisms of Human Meningomyelocele

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $1,390,585

## Abstract

Project Summary – Overall: Developmental Mechanisms of Human Meningomyelocele
The central goal of this Program Project application is to understand mechanisms of Meningomyelocele (MM),
the most severe neural tube defect (NTD) compatible with survival, a condition in which folic acid (FA)
fortification has had a major impact on disease risk. This PPG is designed to advance biomedical knowledge
and make a high impact on our understanding of the molecular genetics of MM across the evolutionary scale,
with the purpose of advancing our ability to determine disease risk, and establish mechanisms by which FA
alters risk. MM is the most common birth defect of the central nervous system, affecting 3.7 per 10,000 live
births, and is one of the high impact conditions prioritized by the NIH for research. In our preliminary data we
have: 1] Constructed a cohort of over 1500 human trios with MM, stratified by whether the child was
conceived in a FA-supplemented geography. 2] Established Xenopus laevis as a high-throughput model
to assess human mutant alleles, gene-gene interactions, and FA exposure. 3] Established a number of
murine NTD models with measured effect of FA on penetrance and expressivity. 4] Demonstrated a proven
track record of applying these tools to study mechanisms of disease. As a result of the extensive preliminary
data presented below, we have formulated this PPG with a two-fold thrust: 1] By taking advantage of the
technical revolution in next generation sequencing and CRISPR genetic engineering, we will uncover and
functionally assess new MM risk factors. 2] By comparing phenotypes across the evolutionary timescale, we
will enhance our understanding of the basic mechanisms of NTDs and the impact of FA. The central theme
running throughout the application is Gene-Environment Interaction (GXE), because of the important role
FA has on MM risk in human, mouse and frog, and because the theme applies to all three Projects and Cores.
Three Cores will carry out essential functions and benefit each Project. 1] Administrative Core to facilitate
communication and provide opportunities for scientific collaboration. 2] Epigenomics Sequencing Core to
provide essential functions in assessing FA-dependent DNA methylation and other impacts on chromatin and
transcription. 3] Bioinformatics Core to provide essential functions in data processing and harmonization,
mutation identification, and custom computational solutions.
Specific Aims of the PPG are: 1] To uncover a host of new developmental causes of MM from this unique
human cohort, as well as from mouse and frog models. 2] To explore mechanisms by which FA reduces
disease incidence in human, mouse and frog. 3] To utilize mechanisms uncovered in mouse and frog NTD
models to inform gene prioritization in human MM. We believe that this PPG will have a major impact on our
understanding of the cellular and molecular mechanisms underlying NTDs, taking advantage of new
breakthrough technology, and will set th...

## Key facts

- **NIH application ID:** 10533735
- **Project number:** 5P01HD104436-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** JOSEPH G GLEESON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,390,585
- **Award type:** 5
- **Project period:** 2020-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10533735

## Citation

> US National Institutes of Health, RePORTER application 10533735, Developmental Mechanisms of Human Meningomyelocele (5P01HD104436-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10533735. Licensed CC0.

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