My overarching scientific goal is to develop a cross disciplinary research program that utilizes zebrafish as a model organism to understand the molecular basis of developmental disorders. I am a tenure track assistant professor at The University of Texas El Paso (UTEP), a Hispanic serving institution, located on the US/Mexican border. UTEP is dedicated to addressing the emerging challenges of the border region and has developed the Border Biomedical Research Center (BBRC), a component of the National Institutes of Health Disparities Research Centers in Minority Institutions Program (RCMI) to expand biomedical research and strengthen the research infrastructure within the region. My research complements the goals of both UTEP and the BBRC, thus I am perfectly positioned to develop a successful cross disciplinary research program. The goal of this K01 mentored career science award is ?to provide a research intensive mentored experience, which will ultimately increase the candidate?s level of competitiveness for future R01 level funding.? To meet this goal, we propose a research intensive training plan, which focuses primarily on improving my publication record and providing high level training in grant writing by utilizing programs sponsored by the National Research Mentoring Network (NMRN) and the American Society for Cell Biology. We will complement these initiatives by enhancing my leadership skills and my professional network. Therefore, at the end of this award, I will have received expert training appropriate to my current position, which will improve my competitiveness for R-level funding. The focus of the current proposal is understand the underlying mechanisms associated with mutations in the HCFC1 transcriptional cofactor. Mutations in HCFC1 cause cobalamin X disorder (cblX), a multiple congenital anomaly syndrome associated with severe neurological and neurodevelopmental deficits. In vitro studies suggest HCFC1 functions to modulate neural precursor differentiation, but these results have not been confirmed in vivo because HCFC1 is present on the X-chromosome in humans and mice and is subject to X- linked compensatory mechanisms which limit the production of homozygous recessive conditional knockout mice. Zebrafish do not have sex chromosomes and therefore represent a unique and powerful system in which to understand the function of in HCFC1. Therefore, the goals of this proposal are 1) to determine the function of HCFC1 in neural precursor specification, proliferation, and differentiation in vivo and 2) to determine whether HCFC1 regulates brain development by modulating the expression of the MMACHC gene. The results of these data will help to identify novel pathways and therapeutic targets for neurological disorders associated with defects in neural precursor function.
Mutations in the HCFC1 gene have been found in patients with multiple congenital anomalies suffering from debilitating neurological impairment and intellectual disability. However, there is a clear gap in our understanding of how mutation of HCFC1 can cause disease. The work proposed here will use zebrafish as a model system to understand how HCFC1 regulates both normal development and disease.
