A BrightFocus National Glaucoma Research grant enabled Michael Elliott, PhD, of the University of Oklahoma Health Sciences Center, to pursue his hunch that flask-shaped parts of cells known as caveolae may act as pressure sensors in the outflow pathway of the human eye. He was among the first to investigate this hypothesis.
More recently, Elliott is exploring the role of caveolae not only in eye drainage, but also in retinal health, and brain function, where there may be a connection to age-related cognitive decline. We caught up with him after his talk at the recent “Basic Science Catalyzing Treatments for Glaucoma” symposium sponsored by BrightFocus, the International Society for Eye Research, and others. (Read a related story on data he presented at the symposium.)
In the following interview, the researcher takes measure of where his original hypothesis now stands, and talks about some surprising new directions where caveolae are taking him.
Q. Caveolae seem to be gaining acceptance as intraocular pressure (IOP) sensors. Were you surprised how quickly your hypothesis caught on?
A. I think the jury is still out about the hypothesis, but the idea makes sense based on work previously done outside of the eye, including studies of caveolae in the cardiovascular system. Caveolae are abundant in the two major cell types found in the eye’s outflow tract, eg, Schlemm’s canal endothelium and the trabecular meshwork. In addition to that, the outflow tract is really an ideal location for caveolae to function as mechanosensors, as this tissue is subject to unique mechanical forces. It is conceivable that caveolae mechanically sense IOP and transduce different signaling pathways in these cell types, as well as, possibly, transduce a variety of signals even in the same cell. They may also protect cells from IOP spike by buffering membrane strain.
Q. How important was BrightFocus funding in giving a start to your research in this area?
A. BrightFocus funding was absolutely essential for me to develop this area of research. While my laboratory has had longstanding interest in lipid rafts and caveolae in the back of the eye (in the retina and retinal pigment epithelium), we had no experience on outflow function and IOP regulation. The ability to develop strong collaborations and interactions with leaders in this area (Drs. Stamer and Tamm), through BrightFocus support, have been crucial in accelerating my learning curve in this research area.
Q. Do gene studies show that CAV1/2 mutations affect additional parts of the eye (in addition to the drainage pathway)?
A. So far, it is not really clear what functional consequences the gene variants at the CAV1/2 locus have, if any, even in regards to the drainage pathway. It is becoming clear that caveolae contribute to other important functions in the eye, including transcellular transport across the blood-retinal barrier, retinal inflammatory signaling, corneal wound healing, and likely other functions.
Q. Your lab website mentions that abnormalities in CAV1 also are linked to a reduction in synaptic connections, and may contribute to age-related cognitive decline. Are you investigating that angle?
A. We have some interest in aging and cognitive decline and are focusing our efforts on vasculature in the CNS (both brain and retina). I would note that other laboratories have been actively working in this area and have suggested caveolae-deficient mice as a model for Alzheimer’s.
Q. Speculatively, do you think caveolae dysfunction relates mostly to CAV1/2 genetic variants, or is it possible that caveolae just wear out over time?
A. This is a really interesting question. There is some evidence that the expression level of caveolins changes with age. However, this appears to be cell context-specific. For example, in the brain, caveolin-1 levels decline with age but in the corneal epithelium they increase. It is not yet clear whether expression of caveolins or caveolae numbers change with age in the outflow tract or retina, but this is an area of interest in my laboratory.
Q. You started out as a retinal researcher and moved over to glaucoma with this project. What’s next, and where do your burning interests lie?
A. I guess I would consider myself a retinal as well as a glaucoma researcher. We have ongoing projects in the retina as well, and the idea of bridging these areas is an interest of mine. In reality, I consider the outflow/IOP project to be a “vascular biology” question, and one that can be informed by research in a variety of areas. The mixing of glaucoma-relevant research in both the anterior and posterior segments of the eye was one of the very beneficial things that came out of the “Basic Science Catalyzing Treatments for Glaucoma” symposium sponsored by BrightFocus, ISER, and others. It proved really interesting and has helped to facilitate interactions between experts in these areas.
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