The applicant, a board eligible pediatrician with a Ph.D. in molecular genetics, is pursuing a fellowship in genetics. He has a long-standing and continued interest in the genetic regulation of metabolism, particularly with regards to the molecular mechanisms involved in mitochondrial function and pediatric mitochondrial disease. In pursuit of these interests, he has sought relevant clinical and research training with a long-term goal of contributing to the understanding of fundamental genetic and molecular mechanisms of mitochondrial function and biogenesis. This application provides a mechanism for achieving an immediate career goal of expanding the applicant's research experience to the fields of Drosophila genetics, development and electrophysiology necessary for the development of novel genetic models for the study of the regulation of mitochondrial function. The purpose of this study is to evaluate the specific functions of isoforms of the Voltage Dependent Anion Channel (VDAC) in Drosophila melanogaster. VDAC, the most abundant protein in the mitochondrial outer membrane, represents the main pathway across this membrane for small metabolites and ions that are essential for mitochondrial-dependent energy metabolism and has been implicated in various regulated cellular processes such as cytochrome-c dependent apoptosis and the permeability transition pore. With the recent annotation of the Drosophila genome, four genes with homology to eukaryotic VDACs have been identified, two of which demonstrate functional complementation of yeast VDAC. These four genes will be characterized in terms of transcript structure, temporal-spatial expression, and in vitro biophysical properties. An allelic series of loss of function mutations for these genes will be generated utilizing both P-element mediated mutagenesis and RNA interference. The specific functions of these Drosophila VDACs will be determined by assessing the consequences of loss of VDAC functions phenotypically on morphological, ultrastructural, cellular, biochemical, and physiological levels. Mutants that demonstrate easily scorable phenotypes will be utilized in genetic enhancer/suppressor screens designed to identify genes that interact with VDACs and are important for mitochondrial function and biogenesis. Through the identification of fundamental, conserved genetic pathways of mitochondrial regulation, this study will contribute to the understanding of mitochondrial function and highlight new genes for future study in mammalian systems as models for human mitochondrial disease and as potential therapeutic targets. The environment in which this study will be performed is uniquely suited for facilitating the applicant's career development plan. The Department of Molecular and Human Genetics at Baylor College of Medicine is renowned for its Drosophila genetics and its collaborative atmosphere. Through a combination of supervised research, scientific interchange, and selected coursework, the applicant will obtain the training necessary for a successful transition to an independent investigator.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Clinical Investigator Award (CIA) (K08)
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Pediatrics Subcommittee (CHHD)
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Coulombe, James N
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Baylor College of Medicine
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Raghavan, Adithya; Sheiko, Tatiana; Graham, Brett H et al. (2012) Voltage-dependant anion channels: novel insights into isoform function through genetic models. Biochim Biophys Acta 1818:1477-85
Rea, Shane L; Graham, Brett H; Nakamaru-Ogiso, Eiko et al. (2010) Bacteria, yeast, worms, and flies: exploiting simple model organisms to investigate human mitochondrial diseases. Dev Disabil Res Rev 16:200-18
Graham, Brett H; Li, Zhihong; Alesii, Erminio P et al. (2010) Neurologic dysfunction and male infertility in Drosophila porin mutants: a new model for mitochondrial dysfunction and disease. J Biol Chem 285:11143-53
Li, Liunan; Shen, Joseph J; Bournat, Juan C et al. (2009) Activin signaling: effects on body composition and mitochondrial energy metabolism. Endocrinology 150:3521-9
Graham, Brett H; Craigen, William J (2005) Mitochondrial voltage-dependent anion channel gene family in Drosophila melanogaster: complex patterns of evolution, genomic organization, and developmental expression. Mol Genet Metab 85:308-17