This Physician Scientist Award proposes two specific objectives.
The first aim i s to allow the principal investigator to develop and apply principals of hypothesis driven laboratory research. A organized plan has been designed which, in Phase I, combines formal courses in molecular and cellular biology in the Departments of Microbiology, Zoology, Avian Sciences, and Biochemistry and Biophysics, University of California, Davis with an intensive laboratory experience under the guidance of the Sponsor. During Phase II, the formal course work will be replaced by independent laboratory investigation. The principal investigator hopes to obtain the necessary training to become an independent, NEI funded investigator without jeopardizing established clinical skills in Vitreoretinal diseases. The second objective focuses on the specific scientific aims of this proposal. Age-related macular degeneration (AMD), the leading cause of blindness in the United States, is an atrophic or exudative deterioration of the photoreceptor-retinal pigment epithelial (RPE)-Bruch's membrane complex. Alterations in the differentiation of RPE cells, such as regulation of basement membrane protein production and cell polarity, are early pathologic events. The pathogenesis of AMD, however, is unknown. Previous studies have focused on later stages of disease. Study of the early events could provide insight into the pathophysiology of AMD. The nonenzymatic glycation of proteins, particularly basement membrane components, has been implicated in the development of aging complications. The long-term goal of this project is to develop an understanding of how glycated basement membranes affect RPE-matrix interaction, and how these changes could lead to the early changes seen in AMD. The hypothesis is that some of the early changes in AMD are initiated by the nonenzymatic glycation of Bruch's membrane. Experiments will utilize in vitro cultures of an established, well characterized human RPE cell line grown under conditions that allow the development of structural and functional polarity. Three ideas will be tested: 1.) do glycated basement membranes alter the subsequent production of basement membrane proteins by RPE cells? 2.) do glycated basement membranes alter the ultrastructural and functional polarity of RPE cells? and, 3.) are these changes mediated by advanced glycation end product receptors?
