The proposal describes a five-year mentored laboratory training experience designed to lead to an independent academic career in clinically-relevant basic science. The applicant holds an M.D. degree, and has completed specialty training and board certification in pediatrics and is currently completing sub-specialty training in Medical Genetics. The career development plan includes a period of mentored research training which will include learning research techniques and concepts supplemented by didactic training, seminars, lab meetings, journal clubs, national and international meetings, an advisory committee and meetings with the mentor. The research environment provides the best intellectual environment and the best technology available and gives the applicant the opportunity to be guided in learning powerful techniques such as electron microscopy and electrophysiology. The research seeks to improve our understanding of peroxisomal biogenesis disorders at the molecular level by focusing on peroxisomal biogenesis in Drosophila. Peroxisomes are ubiquitous organelles in eukaryotes, generated by a set of evolutionarily conserved proteins encoded by the pex genes. Mutations in pex loci in humans lead to Peroxisomal Biogenesis Disorders (PBD), diseases with devastating neurologic consequences. The nervous system complications of PBD have been characterized but their mechanism is not known. Drosophila provides a good model system to add to our knowledge of peroxisomal biogenesis defects. Very little is known about the pex genes in Drosophila. We have selected pex2 and pex16 for analysis. Because of the novelty of this approach very minimal tools are available to study peroxisomes in Drosophila, we will therefore generate additional tools to allow for a precise and thorough analysis of pex2 and pex16 including null alleles, tagged genomic constructs, and assays for the characterization of peroxisome structure and function. We will explore the interaction of peroxisomes with other organelles by testing the hypothesis that peroxisomal loss affects mitochondrial function. Finally, we will build on our preliminary data showing electrophysiologic defects in pex16 P-element insertion mutants by defining the mechanisms by which defective peroxisomal biogenesis lead to exocytic defects in synaptic transmission. This research will create a broader understanding of the effect of peroxisomal biogenesis on the nervous system. This could have clinical implications for patients with peroxisomal disorders. This research will also occur in an environment dedicated to training the applicant to pursue this research further as an independent scientist.
This research studies a group of diseases in which the patient lacks an important cellular organelle named peroxisomes leading to problems in body chemistry. Researchers use fruit flies with similar genetic alterations to study the problems that result from lacking peroxisomes. The research could lead to a better understanding of these diseases for which there are no effective treatments.
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|Braverman, Nancy E; Raymond, Gerald V; Rizzo, William B et al. (2016) Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab 117:313-21|
|Bacino, Carlos; Chao, Yu-Hsin; Seto, Elaine et al. (2016) Dataset for a case report of a homozygous PEX16 F332del mutation. Data Brief 6:722-7|
|Chao, Yu-Hsin; Robak, Laurie A; Xia, Fan et al. (2016) Missense variants in the middle domain of DNM1L in cases of infantile encephalopathy alter peroxisomes and mitochondria when assayed in Drosophila. Hum Mol Genet 25:1846-56|
|Wangler, Michael F; Yamamoto, Shinya; Bellen, Hugo J (2015) Fruit flies in biomedical research. Genetics 199:639-53|
|Bacino, Carlos; Chao, Yu-Hsin; Seto, Elaine et al. (2015) A homozygous mutation in PEX16 identified by whole-exome sequencing ending a diagnostic odyssey. Mol Genet Metab Rep 5:15-18|
|Xia, Fan; Bainbridge, Matthew N; Tan, Tiong Yang et al. (2014) De novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea. Am J Hum Genet 94:784-9|
|Yamamoto, Shinya; Jaiswal, Manish; Charng, Wu-Lin et al. (2014) A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases. Cell 159:200-14|
|Wangler, Michael F; Gonzaga-Jauregui, Claudia; Gambin, Tomasz et al. (2014) Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome. PLoS Genet 10:e1004258|
|Wangler, Michael F; Chavan, Rishikesh; Hicks, M John et al. (2013) Unusually early presentation of small-bowel adenocarcinoma in a patient with Peutz-Jeghers syndrome. J Pediatr Hematol Oncol 35:323-8|
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