3D Genome Disruption in Fetal Alcohol Spectrum Disorder: Toward Diagnostic and Therapeutic Targets.

About This Grant

PROJECT SUMMARY/ABSTRACT This proposal presents a five-year research and career development plan that will allow me to achieve my long-term goal of becoming an independent physician scientist focused on developing and deploying diagnostics and treatments to children living with Fetal Alcohol Spectrum Disorder (FASD). The proposal builds on my previous research and clinical experience in FASD to uncover the role of alcohol as an epigenetic disruptor in the mechanism of FASD. Even though it is the most common cause of preventable neurodevelopmental delay in the United States, the mechanism by which alcohol causes FASD is poorly understood. This gap has resulted in barriers to both diagnosis and treatment. There is no molecular test for FASD, which leads to delayed diagnosis and missed opportunities for intervention. Furthermore, there is no molecularly targeted therapeutic routinely available, making treatment dependent on behavioral and developmental therapies alone. My scientific objective is to identify the ethanol-induced epigenetic alterations responsible for aberrant downstream gene expression of neurodevelopmental pathways. DNA methylation, one aspect of epigenetic regulation, is known to be disrupted in response to prenatal alcohol exposure, but other aspects of the epigenome in FASD remain largely unexplored. This proposal will determine the ability of alcohol to disrupt chromatin organization, a second epigenetic feature, and the resulting consequences on gene expression and neurodevelopment. My central hypothesis is that prenatal alcohol exposure causes a long-term and persistent distortion to the 3D organization of chromatin and alters gene expression in a cell type- and region-specific manner within the brain. I have developed three specific aims to test this hypothesis: 1)Determine the molecular mechanism of ethanol-induced chromatin disruption; 2) Determine cell type-specific chromatin alterations in FASD-relevant brain regions; 3) Identify an epigenetic signature for FASD. My career development objective is to achieve scientific independence by developing the skills required for R01 funding and transformative contributions to the FASD field. I have developed a Career Development Plan focused on three specific short-term goals: 1) To achieve increased command of the bioinformatics techniques required for the genome-wide assessment of genetic and epigenetic alterations in FASD; 2) To develop expertise in clinical research and incorporate this into my FASD diagnostic clinic; 3) To advance my professional and career development by developing targeted professional mentoring, integrating into the larger scientific community, and progressing toward independent funding. In total, the successful completion of this career development program will allow me to develop into an exceptional physician scientist focused on improving the care of children with FASD and continuing to grow a research program that addresses the critical unmet need for diagnostic and treatment options.