Mechanisms underlying the effect of metal exposures on neurodevelopment
Disruption of neurodevelopment and cognitive function early in life due to environmental exposures can have lifelong impacts. The fetal period is a time of heightened vulnerability. Mechanism of early susceptibility is not fully understood, but may be explained, in part, by environmental impact on neural stem cells (NSCs). As the progenitor cells of the central nervous system, NSCs play an essential role in shaping the developing brain and disruption of this process by environmental exposure may lead to deficits later in life. Prenatal or postnatal exposure to environmental perturbation such as malnutrition, pollution, and heavy metals has been associated with low IQ and impaired neurobehavioral and cognitive functions. However, the molecular mechanisms by which environmental factors impact NSC function and early brain development remain poorly understood.
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Roles of placenta/placenta-derived extracellular vesicles on brain development
Placental trophoblasts are a major cell type of placenta and play important roles in many critical processes during pregnancy, including implantation, hormone production and regulation, immune protection of the fetus, and nutrient supply. The cells also play an important role in mediating the communication between the mother and the fetus including fetal brain development. The cells actively release extracellular vesicles (EVs), nano-sized (.05-1 μm) membrane-bound vesicles, into the maternal and the fetal circulation. EVs shuttle cargoes of bioactive molecules, such as proteins, lipids, and nucleic acids, from trophoblasts to the recipient cells, modifying gene expression and biology in the cells. Growing evidence indicates that EVs reach fetal neural cells after crossing the blood-brain barrier (BBB).
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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, 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
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