Present Research

Our long-term goals are to understand how membrane organization in retinal cells regulates or modulates cellular signaling in normal physiology and under pathological conditions. There are two major areas of interest that are currently being pursued in my laboratory: 

      1.  Regulation of blood-retinal barrier permeability by caveolin-1

A robust and intact blood-retinal barrier (BRB) is essential for normal retinal function and loss of barrier properties are pathological hallmarks of three major causes of blindness: age-related macular degeneration (AMD); diabetic retinopathy; and retinopathy of prematurity.  Recent evidence from our laboratory indicates that caveolin-1 (Cav-1), an integral protein component of specialized lipid microdomains called caveolae, is essential to maintain a normal BRB. Cav-1 is expressed in several retinal cell types including the retinal vascular endothelium (RVE) and retinal pigment epithelium (RPE) where it displays a unique apical and basolateral localization. In mice in which the Cav-1 gene has been deleted, we have recently observed leakage of serum proteins into the retina and vitreous of Cav-1 null mice. This increased permeability was also detectable by magnetic resonance imaging (MRI). In addition, Cav-1 null mice display reduced retinal function as indicated by electroretinography (ERG). This reduced function cannot be explained by the direct effect of Cav-1 deletion on photoreceptors as responses were normal in suction electrode recordings from isolated rods. This suggests that changes in the local environment of the photoreceptors, perhaps due to increased outer (RPE) BRB permeability, results in reduced ERG responses. Our results clearly indicate that Cav-1 expression is essential for BRB integrity but the mechanism is not known. We are currently using a variety of molecular, cell biological, electrophysiological, and biochemical techniques to understand the mechanism of regulation of BRB permeability by Cav-1.

2.  Role of membrane domains in photoreceptor structure and function

The “lipid raft” hypothesis has not yet been rigorously tested in photoreceptors or other retinal cells. A goal of the proposed experiments is to develop in vivo models to study lipid domains and their components in a physiologically-relevant context. We have established biochemical analyses, including lipidomics and proteomics, to identify putative domain components isolated from photoreceptor membranes. However, in the vision field, the present understanding of the in vivo importance of membrane domains has been limited by the almost exclusive use of such biochemical methodologies that rely upon isolation of detergent-resistant membranes, an in vitro, “approximation” of lipid rafts in cell membranes. What are needed are approaches to manipulate and analyze rafts in living and functioning retinas. This is a goal of this difficult project and toward this aim we have previously developed transgenic frogs that express raft proteins, e.g., Cav-1, specifically in photoreceptors. In collaboration with Dr. Xi-Qin Ding, we are presently examining the functional consequences of “raft” lipids on photoreceptor protein function.

Curriculum Vitae

Full CV can be accessed here.