Grant Abstract: Gene Nutrient Interactions in Neural Tube Defects

Grant Number: 5R01HD059120-09
PI Name: Stover
Project Title: Gene Nutrient Interactions in Neural Tube Defects

Abstract: The mechanisms and associated pathway(s) underlying folate- and vitamin B12-responsive pathologies are unknown, but mouse models implicate impaired thymidylate (dTMP) synthesis as a common link. We have initiated computational modeling/simulation approaches to enable rapid testing of assumptions related to the critical factors, modifiers and/or interactions that best predict dTMP synthesis capacity and guide empirical research that leads to nutritional interventions to prevent genome instability. The hybrid approach models the intrinsic stochastic behavior in Folate-Mediated One-Carbon Metabolism (FOCM), identifies the location of noise within the network that alters metabolic outputs, and manages combinatorial complexity resulting from reactions/interactions that would otherwise be impossible to elucidate. Hybrid stochastic simulation will help us to understand how these factors combine to affect nuclear dTMP synthesis rates and genome stability, and how these rates compare to rates of dTTP-incorporation into DNA, since these two processes are physically and potentially kinetically linked. The computational model will enable prediction of key FOCM modifiers and thereby guide ongoing empirical research associated with the parent R01.

Specific Aim 1: To quantify rates of dTMP synthesis relative to total dTTP requirements during DNA replication using hybrid stochastic simulations.

Specific Aim 2: To identify and characterize the determinants and dynamics of dTMP synthesis and uracil incorporation into DNA at sites of DNA synthesis using hybrid stochastic simulations.

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