Structural and molecular basis for degenerative diseases of the retina

Our laboratory's primary research interests revolve around the structural and molecular basis for degenerative diseases of the retina, with particular focus on the retinal pigment epithelium in Best disease and the choriocapillaris in age-related macular degeneration. Best disease is a relatively rare but potentially devastating form of macular degeneration. Over one hundred different mutations in the responsible gene, VMD2/bestrophin, can result in this autosomal dominant disorder. Bestrophin most likely functions as a chloride channel and thus may regulate the ionic milieu in the subretinal space. We are using both in situ approaches and in vitro approaches to understand how specific mutations affect behavior of the mutant protein and to examine the regional distribution of the bestrophin protein in normal eyes, as well as to evaluate genotype-phenotype relationships for eyes with Best disease. Age-related macular degeneration (AMD) is a common cause of blindness that affects as many as one in three elderly individuals to some degree. With the increasing median age of the population, it is widely appreciated that the impact of AMD will worsen in the coming years. Recent genetic and histopathologic studies indicate that AMD is associated with inflammation, and there is strong evidence for leukocyte extravasation in the pathogenesis of the disease; however the role of the vasculature in recruiting leukocytes during these inflammatory events is poorly understood. The choriocapillaris is the capillary bed responsible for nourishing the photoreceptor cells of the retina, and is the most likely source for recruiting leukocytes in AMD. We are interested in determining the biological changes of the choriocapillaris in eyes with macular degeneration by examining human donor tissue, as well as cell surface molecules that differ between normal and neovascular endothelial cells. In addition to descriptive studies in situ, we are interested in characterizing the molecular responses of human choroidal endothelial cells (cultured from human eyes) to the types of microenvironmental pro-inflammatory challenges that occur in macular degeneration, including exposure to complement components and products of extracellular matrix protein degradation. Molecular and functional assays of human choroidal EC are performed in the presence or absence of these AMD microenvironment challenges. In addition we have several active collaborations in The University of Iowa, evaluating animal models of inherited retinal diseases, and assisting other faculty in answering histological questions in the eye.

Department/Program Affiliations:
Genetics
Molecular Medicine
Ophthalmology and Visual Sciences