Research Interests: Understanding the role of membrane organization on the structure and function of retinal cells under normal and pathological conditions.
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. We have several projects 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; 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, Müller glia, and retinal pigment epithelium. In mice in which the Cav-1 gene has been deleted, we have observed leakage of serum proteins into the retina and vitreous of Cav-1 null mice. 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 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 including conditional cell-specific deletion to understand the mechanisms by which Cav-1 regulates BRB integrity.
2. Role of caveolins/caveolae in intraocular pressure and aqueous outflow regulation.
Elevated pressure in the eye is the major risk factor in developing primary open angle glaucoma (POAG). Intraocular pressure (IOP) is controlled by the rate of production and drainage of aqueous humor. In the normal eye, the drainage process is tightly regulated in order to maintain optimal IOP. In many forms of glaucoma, this drainage system does not work effectively leading to elevations in IOP. The mechanisms that tightly regulate the rate of fluid drainage are unknown but are likely to involve a mechanical pressure sensor that causes drainage to increase if IOP increases and resists drainage if IOP is too low. The nature and cellular location of this “molecular pressure-stat” is unknown. Recently, human gene association studies have linked the CAV1 gene to increased risk of developing POAG. This gene, which my laboratory has been studying for some time in ocular tissue, is known to form specialized domains in cell membranes called “caveolae”. There is emerging evidence that these domains are sensors for mechanical changes in cell membranes such as those that might result from increases in IOP. We hypothesize that caveolae may be the sensor that regulates fluid drainage and that mutations in the CAV1 gene may render this sensor defective. We are currently testing this hypothesis.
3. Proteomic mapping of diabetic retinal vascular membranes.
The goal of this project is to test the hypothesis that diabetic tissue microenvironments modulate protein expression in vascular endothelium, in vivo, and that these changes can be assessed by comparative mass spectrometry to generate tissue-specific proteome maps from diabetic and control vasculature. The long term goal is to identify novel therapeutic targets for diabetic retinopathy (DR) and nephropathy (DN) and to identify shared and divergent disease mechanisms in these tissues. This will be accomplished by analyzing diseased and control retinal and renal vascular endothelial membranes isolated in purity from an in vivo model of diabetic vascular disease. By focusing on the primary, dysfunctional cell type, this innovative discovery-based approach will significantly reduce sample complexity allowing for elucidation of novel disease mechanisms and for identification of endothelium-specific therapeutic targets for DR and DN.
4. Role of caveolins in corneal stem cell biology/corneal wound healing.
This is a collaborative project with Dr. Alex Cohen, MD, PhD, Assistant Professor of Ophthalmology at OUHSC/Dean McGee Eye Institute. The goal of this project is to understand the molecular mechanisms involved in corneal limbal stem cell-derived epithelial wound healing and to develop strategies to modify the proliferative capacity of adult corneal epithelial stem cells (CESCs) with the long term goal of advancing the field of stem cell therapy for corneal blindness.
5. Altered signal processing in lipid rafts and synaptic dysfunction in brain aging.
This is a collaborative project with Dr. Ferenc Deak, MD, PhD at the Reynolds Oklahoma Center on Aging. Advances in medicine have dramatically prolonged the lifespan of human beings with recent estimates suggesting that the number of people over the age of 90 years in the United States will double to ~2 million in this decade. This lifespan increase is not without cost and the emerging problem is an increased number of individuals with age related cognitive impairment and even dementia in this aging population. As such, efforts are necessary to improve the quality of life of our rapidly expanding aging population. An important potential mechanism responsible for age-related cognitive impairment is a reduced number of functional synaptic connections between nerve cells. The goal of this project is to examine novel molecules, caveolin-1 (Cav-1) and synaptobrevin-2 (SVB2) that control synaptic dysfunction in aging. We hypothesize that these molecules interact functionally and that combined age-related declines in their expression potentiates synaptic dysfunction and cognitive decline.
National Institutes of Health / National Eye Institute
American Diabetes Association
Alcon Research Institute
Oklahoma Center for Adult Stem Cell Research
Reynolds Oklahoma Center on Aging
Research to Prevent Blindness, Inc
Full CV can be accessed here.
Human Biology, Division of Biological Sciences, University of Kansas, Lawrence, KS.
Physiology and Cell Biology, Department of Molecular Biosciences, University of Kansas, Lawrence, KS.
Postdoctoral Fellowship, Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK