Monday, May 19, 2025
5/19/2025
Investigating the Role of Apoptosis in Early Life Vulnerability to Lead-Induced Neurotoxicity - PROJECT SUMMARY/ABSTRACT The public health crisis in Flint, Michigan has resurfaced concerns about exposure to lead, a neurotoxicant that causes long-term brain damage in children. Despite its known dangers, the biological mechanisms that make children more vulnerable to exhibiting neurocognitive impairments after lead exposure remain unknown. Apoptosis regulation is one potential mechanism, as neurodevelopment requires apoptosis to prune superfluous neurons and lead has been shown to trigger apoptotic cell death. Our laboratory has recently discovered that neural cells are “primed for apoptosis” during the postnatal brain maturation period. The pro- apoptotic protein BAX, which causes mitochondrial permeabilization and cytochrome c release to initiate apoptosis, facilitates this sensitivity. More mature neural cell types are less prone to apoptosis as BAX expression decreases with age. We believe that heightened BAX expression and apoptotic priming in the young brain drive lead-induced apoptosis and consequent neurocognitive impairments, which may be prevented by blocking apoptosis. This F31 research proposal aims to determine if suppressing BAX-mediated apoptosis in neural cell populations can reduce the neurotoxic effects of early-life lead exposure and improve neural cell survival and function. Our central hypothesis is that lead induces pro-apoptotic signaling in the brain regardless of age, but young brain tissue is more likely to exhibit signs of neural cell apoptosis due to higher BAX expression and apoptotic priming than adults, increasing vulnerability to neurocognitive impairment. I proposed to test this in three aims: (1) elucidate the mechanism of lead-induced neural cell apoptosis in differentiating human and mouse cells; (2) investigate how the timing of initial lead exposure during development affects the developing brain; and (3) investigate how BAX knockout protects against neurocognitive impairments. My training plan aims to help me achieve my short-term career goal of attaining a prestigious postdoctoral fellowship, which, upon completion, would prepare for my long-term goal of establishing my laboratory as a tenure-track professor at a high-ranking school of public health, where I aspire to conduct research in developmental neuroscience and environmental neurotoxicology. Therefore, I am eager to contribute to manuscripts, publish first-author papers, and share my discoveries in seminars series and at national conferences. I am also committed to modest amounts of teaching, curriculum development, outreach, and mentoring other students. I understand that these goals are not easily achieved and am grateful for the support offered by my sponsors and the members of my Science Advisory and Career Mentoring Committees. Working together, we have the potential to achieve significant progress in the areas of cell death, neuroscience, public health, and environmental health.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).