The long-term focus of my research program has been to understand the molecular pathogenic mechanisms of human genetic diseases. Our recent efforts have been targeted towards human genetic retinal diseases. Genetic alterations leading to retinal diseases are a leading cause of blindness in the world and understanding the molecular basis of the alterations offers the possibilities of devising new treatment strategies. In our studies we apply a broad array of biochemical techniques combined with genetic methods, in particular genetic manipulations that lead to generation of transgenic, gene-knockout and gene-knockin mutant mice. The genetically modified mice, we have generated, have become very useful models for studies of human pathologies.
We have generated mouse models that carry mouse genes with human mutations that are responsible for, or have been shown to be associated with, human retinal pathologies, including retinitis pigmentosa, Stargardt-3 macular dystrophy and age-related macular degeneration. Characterization of the mutant mouse models shows that they replicate many of the molecular, morphological and functional changes that are seen in the eyes of human patients. Our studies of a mouse model of dominant retinitis pigmentosa, a relatively common human disease caused by mutations in the rds/peripherin gene, identified reduced mutant rds/peripherin protein stability as a pathogenic defect which leads to structural abnormalities and degeneration of retinal photoreceptors.
Most recently we generated a mouse model of Stargardt disease-3 macular dystrophy, a human early-onset dominant macular degeneration. Biochemical studies in these mice identified the pathogenic retinal defect as a deficiency of a unique group of phosphatidylcholine lipids in the photoreceptor outer segments. DHA is the most abundant polyunsaturated fatty acid in the retina and was long thought to have a role in STGD3 pathology. Our mouse studies showed that DHA levels were unaltered in the presence of the pathogenic mutation. However, PC lipids containing acyl residues of polyunsaturated extremely long chain C32-C36 fatty acids were selective depleted. These studies also revealed that these same fatty acids were essential for maintenance of the barrier function of the skin, since in their absence mice died shortly after birth. Studies are now ongoing to further understand the biological function of these unique lipids.
To gain an understanding of the molecular changes in age-related macular degeneration, we recently generated mice that carry sequence variants of complement factor H. The presence of different sequence variants of CFH has been shown to be associated with age-related macular degeneration in humans. In summary, the goal of our research is to identify molecular mechanisms of human pathologies and based on that knowledge to design and test potential treatments.
RESEARCH INTERESTS
Molecular Mechanisms of Human Genetic Diseases
RECENT PUBLICATIONS
Kedzierski W., Bok D. and Travis G.H., "Transgenic analysis of rds/peripherin N-glycosylation: Effect on dimerization, interaction with rom1, and rescue of the rds null-phenotype" J Neurochemistry, 72:430, 1999
Kedzierski W., Nusinowitz S., Birch D.G., Clarke G., McInnes R.R., Bok D., and Travis G. H., "Deficiency of rds/peripherin causes photoreceptor death in mouse models of digenic and dominant retinitis pigmentosa" PNAS, 98:7718, 2001
A McMahon, IA Butovich, NL Mata, M Klein, R Ritter, J Richardson, DG Birch, AO Edwards, W Kedzierski, "Retinal Pathology and Skin Barrier Defect in Mice Carrying a Stargardt Disease-3 Mutation in Elongase of Very Long Chain Fatty Acids-4" Molecular Vision, 13:258-272, February 2007
A McMahon, SN Jackson, AS Woods, W Kedzierski, "A Stargardt Disease-3 Mutation in the Mouse Elovl4 Gene Causes Retinal Deficiency of C32-C36 Acyl Phosphatidylcholines" FEBS Letters, 581:5459-5463, November 2007
I Nir, W Kedzierski, J Chen, GH Travis, "Expression of Bcl-2 protects against photoreceptor degeneration in rds mice" Journal of Neuroscience, 20:2150, July 2000
SIGNIFICANT PUBLICATIONS
Kedzierski W., Weng J. and Travis G.H., "Analysis of the rds/peripherin - rom1 complex in transgenic photoreceptors that express a chimeric protein." JBC, 274:29181, 1999
Kedzierski W., Nusinowitz S., Birch D.G., Clarke G., McInnes R.R., Bok D., and Travis G. H., "Deficiency of rds/peripherin causes photoreceptor death in mouse models of digenic and dominant retinitis pigmentosa." PNAS, 98:7718, 2001
W Kedzierski, M Lloyd, DG Birch, D Bok, GH Travis, "Generation and analysis of transgenic mice expressing P216-L-substituted rds/peripherin in rod photoreceptors" Investigative Ophthalmology and Visual Science, 38:498, July 1997
A McMahon, IA Butovich, NL Mata, M Klein, R Ritter III, J Richardson, DG Birch, AO Edwards, W Kedzierski, "Retinal pathology and skin barrier defect in mice carrying a Stargardt disease-3 mutation in elongase of very long chain fatty acids-4" Molecular Vision, 13:258, February 2007
A McMahon, SN Jackson, AS Woods, W Kedzierski, "A Stargardt disease-3 mutation in the mouse Elovl4 gene causes retinal deficiency of C32-C36 acyl phosphatidylcholines" FEBS Letters, 581:5459, November 2007
Point and right click (click and hold for Mac users) your mouse onand select "Save this link (or target) as..." option to save the file to your local computer.
and select "Save this link (or target) as..." option to save the file to your local computer.