Functional association of genetic variants with neurodevelopment in children
This project is aimed to investigate the association of genetic variants with neurodevelopmental outcomes in children and to test the functional effects of the genetic variants in NSC function utilizing CRISPR-based single base editing technique. Furthermore, the effect of genetic variants in the regulation of NSC responses to metal exposure will be determined. I hypothesize that genes or microRNAs, which are identified as functionally important in neural stem cell function (Project 1), will have genetic polymorphisms that associate with metal-impaired neurodevelopment in susceptible children. In collaboration with genetic epidemiologists, we will identify SNPs of most common variations in target genes/microRNAs then test the association between these SNPs and neurodevelopmental outcomes. For example, our recent study identified novel suppressors of arsenic (As)-induced endoplasmic reticulum stress including microRNA(miR)-124 (Panganiban and Park, 2019, PNAS). We further showed that miR-124 protects against As toxicity in human neural cells and its genetic polymorphisms are associated with neurodevelopmental outcomes in children (Park et al., 2020, Scientific Reports).
An ultimate goal of genetic association studies is to establish that a particular variant not just associates with but causes the phenotype. A direct way to establish the causal role of a variant is to genetically alter the allele followed by phenotypic assessment of the change. Using CRISPR-based precise gene editing technique. We will assess the roles of associated variants in NSC function.
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