# Risk Genes and Environmental Interactions in Neural Tube Defects

> **NIH NIH P01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $1,287,230

## Abstract

RISK GENES AND ENVIRONMENT INTERACTIONS IN NTDS
 Neural tube defects (NTDs) arise from a complex interplay of multiple genes and environmental
exposures. In human populations, folic acid (FA) supplementation can prevent up to 70% of NTD occurrences-
-including anencephaly and spina bifida—by as yet unknown mechanism(s). Nevertheless, FA fails to benefit
at least a third of families and recent data suggest that in some specific genetic contexts, FA may be
deleterious to the developing embryo. Clearly, families would be far better served if their individual risks could
be accurately assessed, including identification of which aspect of the FA metabolic pathway--or which
supplement involving another pathway entirely--would provide the most benefit to them, so that NTD
prevention strategies could be optimized according to individual genetic risk factors.
 This program aims to improve NTD risk assessment and prevention by integrating advanced human
genomics with biological paradigms in humans and mice for identifying key gene-environment interactions.
 Project 1 (Ross PI with Finnell & Gross) has accumulated 200 whole genome sequences (WGS) from
cases and 200 controls and has identified rare nonsense, frameshift and non-coding variants associated with
spina bifida. In the renewal, we will employ a powerful high throughput method using molecular inversion
probes (MIPs) to resequence a replication cohort of over 2,000 NTD cases. Cutting edge CRISPR-Cas9
dependent genome editing in hESCs and mice will probe the functional impact of identified variants on
neuroepithelial cell polarity, proliferation, and the generation of reactive oxidative/nitrosative species (RONS).
 Project 2 (Gross PI with Ross & Finnell) will test the hypothesis that a major role for folate protection
against NTD is to suppress the generation of RONS. They will employ a novel untargeted stable isotope
method to trace folate-mediated 1-C trafficking in NTD-susceptible mouse models. In addition, they will employ
a novel redoxome platform to quantify oxidatively-modified small molecules in NTD prone mice. With Projects
1&3, they will examine the impact of identified NTD associated human variants on cellular redox status and 1-
C trafficking and the extent to which supplementation with small molecules can modulate these actions.
 Project 3 (Finnell PI with Gross & Ross) will examine the interaction of genetic variants and RONS to
disrupt signaling pathways and cause cell damage during NT closure. They will test the ability of a human
NTD-associated variant in NO synthase, NOS3, to increase ROS peroxynitrite in cells due to the
phosphorylation of NOS3 on Ser633. It will test whether mitochondria are a major source of RONS during
neurulation. Together, Projects 1, 2, & 3 will help define interactions of maternal/embryonic genetics, nutritional
status and 1-C metabolism with NTD risk, using extensive human genomics, proteomics/metabolomics, and
CRISPR-Cas9-dependent genome editing in hESCs,...

## Key facts

- **NIH application ID:** 9931241
- **Project number:** 5P01HD067244-10
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** MARGARET ELIZABETH ROSS
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,287,230
- **Award type:** 5
- **Project period:** 2011-09-23 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931241

## Citation

> US National Institutes of Health, RePORTER application 9931241, Risk Genes and Environmental Interactions in Neural Tube Defects (5P01HD067244-10). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9931241. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*