Faculty

Michael H. Elliott, PhD, FARVO

Our research program is focused on understanding how discrete regions of cell membranes, broadly called “lipid rafts”, influence ocular pathology and physiology. The conceptual framework of lipid rafts places them as organizing nexuses for a variety of cellular signaling events. The goal of our studies is to identify ocular disease-relevant molecular networks localized to lipid rafts that could be modified by raft manipulation. As disease processes are complex, involving significant cross-talk between many signaling pathways, understanding and targeting the nexus, the lipid raft itself, either by disrupting or enhancing its structure/function could be therapeutic.

1. Role of caveolin-1 in neurovascular inflammation in the retina. Neurovascular inflammatory processes are critical events in a host of retinal diseases including age-related macular degeneration and diabetic retinopathy. We have found that caveolin-1, a protein abundantly expressed in retinal vascular cells and the primary retinal glia (Müller glia), plays important roles in the maintenance of the blood-retinal barrier and in control of innate inflammatory responses. Intriguingly, caveolin-1 promotes activation of Toll-like receptor-4 signaling in the retina. We are currently examining a novel molecular mechanism for this control that involves regulation of the stability of TNF Receptor Associated Factor-3 (TRAF3).
2. Caveolae as mechanosensors for intraocular pressure homeostasis. Glaucoma is a major cause of blindness worldwide with primary open angle glaucoma being the most prevalent form. The primary risk factor in glaucoma, intraocular pressure, is regulated by control of the rate of drainage of aqueous fluid from the eye from a unique vascular network called the conventional outflow pathway. While the molecular mechanisms that control conventional outflow are not well understood, homeostatic responses of conventional outflow cells to mechanical stimulation are crucial. Polymorphisms in the CAV1/2 genes, which encode essential proteins for a putative membrane mechanical sensor, caveolae, associate with POAG and elevated IOP. Genetic deletion of CAV1 in mice ablates caveolae, resulting in ocular hypertension due to functional defects in conventional outflow function. The mechanism for this defect and the connection between disease-associated polymorphisms and caveolae function are not understood. This project addresses these important knowledge gaps.
3. Novel regulators of ocular wound healing. The clear cornea is the outermost structure of the eye, which transmits light to the inside of the eye.  The cells responsible for maintaining the corneal surface are called limbal stem cells.  These cells normally divide and proliferate to repopulate the cornea as well as heal the surface after a wound.  Without proper wound healing, corneal blindness can result.  We have found that caveolin-1 regulates the process of wound healing and that loss of this protein in a knockout mouse model leads to faster healing.  Evidence suggests that caveolin-1 works by regulating stem cell proliferation.  Our intent is to better understand this process and develop medications that can mimic the loss of caveolin-1 and accelerate wound healing.
4. Novel mechanisms of retinal vascular aging. Through collaboration with investigators at the Reynolds Oklahoma Center on Aging we have made the novel observation that normal, “physiological” aging results in focal loss of contractile smooth muscle cells on retinal arterioles. Our results provide a cellular mechanism for prior clinical studies showing vascular microirregularities and defects in vascular responsiveness in aged human subjects. We are currently examining the molecular mechanisms for these age-related vascular changes as they may contribute to age-related retinal and cerebrovascular complications.