The ultimate goal of this proposal is to create new, more effective means of preventing, diagnosing and treating neural degeneration associated with Parkinson's disease (PD). PD is a chronic progressive disorder with a lifetime prevalence of 1-2% and is thought to be caused by degeneration of specific neurons in the brain. Based on familial inheritance studies, mutations in the human parkin gene have been associated with juvenile onset parkinsonism. However, the exact role of parkin in the pathogenesis of PD has not been clearly established. While the best approach for identifying new therapies for PD is to have a complete understanding of the molecular and genetic mechanisms that lead to the disease state, methods for genetic analysis in mammals are time-consuming and expensive. Fortunately, the fruit fly Drosophila melanogaster offers an unparalleled combination of powerful molecular and genetic tools and has proven to be an excellent in vivo animal model system for developmental and degenerative processes directly relevant to human biology. Drosophila has been successfully used to study neurological disorders such as Huntington's disease, Spinocerebellar Ataxia 3 and PD. Moreover, we have identified a Drosophila homolog of human parkin, dparkin, which will generate powerful tools for deciphering the mechanisms of parkin function. We propose to exploit the power of Drosophila genetics to determine the loss- and gain-of-function effects of dparkin mutants. Moreover, we will conduct genome-wide genetic screens to identify new, conserved genes that interact with dparkin to cause neural degeneration. These experiments outline a strategy for the rapid elucidation of a pathway critical to the pathogenesis of Parkinson's disease that cannot be matched by any mammalian system. As new genes are identified and characterized, we will then study vertebrate homologs of such genes both in humans and in mice.
Dr. Graeme Mardon received his B.S. in 1980 with a double major in Biology and Chemistry from Haverford College. Following a four-year research associate position with Dr. Harold E. Varmus studying the viral oncogene src at the University of California in San Francisco, Dr. Mardon began graduate school at the Massachusetts Institute of Technology in 1984. He received his Ph.D. in 1990 in the laboratory of Dr. David C. Page where he studied genes located in the sex-determining region of the mouse Y chromosome. Dr. Mardon then conducted his postdoctoral work with Dr. Gerald M. Rubin at the University of California in Berkeley from 1990 to 1994 studying genes required for normal eye development in the fruit fly Drosophila melanogaster. Dr. Mardon joined the faculty at Baylor College of Medicine in 1994 where he has established a strong program studying the molecular genetics of developmental neurobiology using both Drosophila and the mouse as animal model systems. While at Baylor, Dr. Mardon has published a series of significant papers concerning a group of conserved genes that control eye development in both Drosophila and humans. This work has established Dr. Mardon as one of the leaders in this field.
Dr. Graeme Mardon received his B.S. in 1980 with a double major in Biology and Chemistry from Haverford College. Following a four-year research associate position with Dr. Harold E. Varmus studying the viral oncogene src at the University of California in San Francisco, Dr. Mardon began graduate school at the Massachusetts Institute of Technology in 1984. He received his Ph.D. in 1990 in the laboratory of Dr. David C. Page where he studied genes located in the sex-determining region of the mouse Y chromosome. Dr. Mardon then conducted his postdoctoral work with Dr. Gerald M. Rubin at the University of California in Berkeley from 1990 to 1994 studying genes required for normal eye development in the fruit fly Drosophila melanogaster. Dr. Mardon joined the faculty at Baylor College of Medicine in 1994 where he has established a strong program studying the molecular genetics of developmental neurobiology using both Drosophila and the mouse as animal model systems. While at Baylor, Dr. Mardon has published a series of significant papers concerning a group of conserved genes that control eye development in both Drosophila and humans. This work has established Dr. Mardon as one of the leaders in this field.