Michael Elliott lab coat portrait (002)

Michael H. Elliott, PhD, FARVO

Appointments:

  • Associate Professor of Ophthalmology
  • Associate Professor of Physiology
  • Member, Oklahoma Center for Neuroscience
  • Member, Harold Hamm Diabetes Center

Training:

  • B.A. Human Biology, University of Kansas
  • Ph.D. Molecular Biosciences, University of Kansas
  • Postdoctoral Fellowship, Department of Ophthalmology, OUHSC

Special Interests:

  • Caveolae and membrane domains in ocular physiology/pathophysiology
  • Neuroprotective and inflammatory signaling in the retina
  • Pathophysiology of ocular hypertension/modulation of intraocular pressure
  • Ocular vascular aging

Research Summary:

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.

Recent and Relevant Publications:

  1. Reagan, A. M., Gu, X., Paudel, S., Ashpole, N. M., Zalles, M., Sonntag, W. E., Ungvari, Z., Csiszar, A., Otalora, L., Freeman, W. M., Stout, M. B., Elliott, M. H. (2018). Age-related focal loss of contractile vascular smooth muscle cells in retinal arterioles is accelerated by caveolin-1 deficiency. Neurobiol Aging, 71, 1-12.
  2. Tarantini, S., Valcarcel-Ares, M. N., Yabluchanskiy, A., Tucsek, Z., Hertelendy, P., Kiss, T., Gautam, T., Zhang, X., Sonntag, W. E., de Cabo, R., Farkas, E., Elliott, M. H., Kinter, M. T., Deak, F., Ungvari, Z., Csiszar, A. (2018). Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood-Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype. J Gerontol A Biol Sci Med Sci, 73, 853-863.
  3. Keller, K. E., Bhattacharya, S. K., Borrás, T., Brunner, T. M., Chansangpetch, S., Clark, A. F., Dismuke, W. M., Du, Y., Elliott, M. H., Ethier, C. R., et al. (2018). Consensus recommendations for trabecular meshwork cell isolation, characterization and culture. Exp Eye Res, 171, 164-173.
  4. Royer, D. J., Elliott, M. H., Le, Y. Z., Carr DJJ (2018). Corneal Epithelial Cells Exhibit Myeloid Characteristics and Present Antigen via MHC Class II. Invest Ophthalmol Vis Sci, 59, 1512-1522.
  5. Masser, D. R., Otalora, L., Clark, N. W., Kinter, M. T., Elliott, M. H., Freeman, W. M. (2017). Functional changes in the neural retina occur in the absence of mitochondrial dysfunction in a rodent model of diabetic retinopathy. J Neurochem, 143, 595-608.
  6. Du, M., Mangold, C. A., Bixler, G. V., Brucklacher, R. M., Masser, D. R., Stout, M. B., Elliott, M. H., Freeman, W. M. (2017). Retinal gene expression responses to aging are sexually divergent. Mol Vis, 23, 707-717.
  7. Oliveira SDS, Castellon, M., Chen, J., Bonini, M. G., Gu, X., Elliott, M. H., Machado, R. F., Minshall, R. D. (2017). Inflammation-induced caveolin-1 and BMPRII depletion promotes endothelial dysfunction and TGF-β-driven pulmonary vascular remodeling. Am J Physiol. Lung Cell Mol Physiol, 312, L760-L771
  8. McClellan, M. E., Elliott, M. H. (2017). Analysis of Fatty Acid and Cholesterol Content from Detergent-Resistant and Detergent-Free Membrane Microdomains. Methods Mol Biol, 1609, 185-194.
  9. Gu, X., Reagan, A. M., McClellan, M. E., Elliott, M. H. (2017). Caveolins and caveolae in ocular physiology and pathophysiology. Prog Retin Eye Res, 56, 84-106.
  10. Elliott, M. H., Ashpole, N. E., Gu, X., Herrnberger, L., McClellan, M. E., Griffith, G. L., Reagan, A. M., Boyce, T. M.*, Tanito, M., Tamm, E. R., Stamer, W. D. (2016). Caveolin-1 modulates intraocular pressure: implications for caveolae mechanoprotection in glaucoma. Sci Rep, 6, 37127. DOI: 10.1038/srep37127
  11. Yu, J. Y., Du, M., Elliott, M. H., Wu, M., Fu, D., Yang, S., Basu, A., Gu, X., Ma, J.-X., Aston, C. E., Lyons, T. J. (2016). Extravascular modified lipoproteins: a role in the propagation of diabetic retinopathy in a mouse model of type 1 diabetes. Diabetologia, 59, 2026-35.
  12. Ding, X.-Q., Thapa, A., Ma, H., Xu, J., Elliott, M. H., Rodgers, K. K., Smith, M. L., Wang, J. S., Pittler, S. J., Kefalov, V. J. (2016). The B3 Subunit of the Cone Cyclic Nucleotide-gated Channel Regulates the Light Responses of Cones and Contributes to the Channel Structural Flexibility. J Biol Chem, 291, 8721-34.
  13. Sethna, S., Chamakkala, T., Gu, X., Thompson, T. C., Cao, G., Elliott, M. H., Finnemann, S. C. (2016). Regulation of Phagolysosomal Digestion by Caveolin-1 of the Retinal Pigment Epithelium Is Essential for Vision. J Biol Chem, 291, 6494-506.
  14. Reagan, A., Gu, X., Hauck, S. M., Ash, J. D., Cao, G., Thompson, T. C., Elliott, M. H. (2016). Retinal Caveolin-1 Modulates Neuroprotective Signaling. Adv Exp Med Biol, 854, 411-8.
  15. Ding, L., Cheng, R., Hu, Y., Takahashi, Y., Jenkins, A. J., Keech, A. C., Humphries, K. M., Gu, X., Elliott, M. H., Xia, X., Ma, J.-X. (2014). Peroxisome proliferator-activated receptor α protects capillary pericytes in the retina. Am J Pathol, 184, 2709-20.
  16. Li, X., Gu, X., Boyce, T. M., Zheng, M., Reagan, A. M., Qi, H., Mandal, N., Cohen, A. W., Callegan, M. C., Carr, D. J., Elliott, M. H. (2014). Caveolin-1 increases proinflammatory chemoattractants and blood-retinal barrier breakdown but decreases leukocyte recruitment in inflammation. Invest Ophthalmol Vis Sci, 55, 6224-34.
  17. Gu, X., Fliesler, S. J., Zhao, Y. Y., Stallcup, W. B., Cohen, A. W., Elliott, M. H. (2014). Loss of caveolin-1 causes blood-retinal barrier breakdown, venous enlargement, and mural cell alteration. Am J Pathol, 184, 541-55.
  18. Gu, X., Reagan, A., Yen, A., Bhatti, F. N., Cohen, A. W., Elliott, M. H. (2014). Spatial and temporal localization of caveolin-1 protein in the developing retina. Adv Exp Med Biol, 801, 15-21.
  19. Chucair-Elliott, A. J., Elliott, M. H., Wang, J., Moiseyev, G. P., Ma, J.-X., Politi, L. E., Rotstein, N. P., Akira, S., Uematsu, S., Ash, J. D. (2012). Leukemia inhibitory factor coordinates the down-regulation of the visual cycle in the retina and retinal-pigmented epithelium. J Biol Chem, 287, 24092-102.
  20. Li, X., McClellan, M. E., Tanito, M., Garteiser, P., Towner, R., Bissig, D., Berkowitz, B. A., Fliesler, S. J., Woodruff, M. L., Fain, G. L., Birch, D. G., Khan, M. S., Ash, J. D., Elliott, M. H. (2012). Loss of caveolin-1 impairs retinal function due to disturbance of subretinal microenvironment. J Biol Chem, 287, 16424-34.
  21. Mandal, M. N., Moiseyev, G. P., Elliott, M. H., Kasus-Jacobi, A., Li, X., Chen, H., Zheng, L., Nikolaeva, O., Floyd, R. A., Ma, J.-X., Anderson, R. E. (2011). Alpha-phenyl-N-tert-butylnitrone (PBN) prevents light-induced degeneration of the retina by inhibiting RPE65 protein isomerohydrolase activity. J Biol Chem, 286, 32491-501.
  22. Wang, J., Xu, X., Elliott, M. H., Zhu, M., Le, Y. Z. (2010). Müller cell-derived VEGF is essential for diabetes-induced retinal inflammation and vascular leakage. Diabetes, 59, 2297-305.
  23. Agbaga, M.-P., Brush, R. S., Mandal, M. N., Henry, K., Elliott, M. H., Anderson, R. E. (2008). Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids. Proc Natl Acad Sci USA, 105, 12843-8.
  24. Ding, X.-Q., Fitzgerald, J. B., Matveev, A. V., McClellan, M. E., Elliott, M. H. (2008). Functional activity of photoreceptor cyclic nucleotide-gated channels is dependent on the integrity of cholesterol- and sphingolipid-enriched membrane domains. Biochemistry, 47, 3677-87.
  25. Elliott, M. H., Nash, Z. A., Takemori, N., Fliesler, S. J., McClellan, M. E., Naash, M. I. (2008). Differential distribution of proteins and lipids in detergent-resistant and detergent-soluble domains in rod outer segment plasma membranes and disks. J Neurochem, 104, 336-52.
  26. Martin, R. E., Elliott, M. H., Brush, R. S., Anderson, R. E. (2005). Detailed characterization of the lipid composition of detergent-resistant membranes from photoreceptor rod outer segment membranes. Invest Ophthalmol Vis Sci, 46, 1147-54.
  27. Elliott, M. H., Fliesler, S. J., Ghalayini, A. J. (2003). Cholesterol-dependent association of caveolin-1 with the transducin alpha subunit in bovine photoreceptor rod outer segments: disruption by cyclodextrin and guanosine 5'-O-(3-thiotriphosphate). Biochemistry, 42, 7892-903.
  28. Davies, S., Elliott, M. H., Floor, E., Truscott, T. G., Zareba, M., Sarna, T., Shamsi, F. A., Boulton, M. E. (2001). Photocytotoxicity of lipofuscin in human retinal pigment epithelial cells. Free Radic Biol Med, 31, 256-65.

Funding Agencies:

  • NIH R01EY028608: Caveolae-based mechanosensors for conventional outflow regulation. Elliott (PI)
  • NIH R01EY019494: Role of Caveolin-1 in the Maintenance of Blood-Retinal Barrier Integrity. Elliott (PI)
  • Oklahoma Center for Adult Stem Cell Research (OCASCR): Role of Cav1 on Maintenance of Corneal Epithelial Stem Cells- A New Therapy. Elliott (PI)
  • Oklahoma Center for the Advancement of Science and Technology (OCAST) HF18-0008: The Role of TRAF3 in Retinal Function and Inflammation (postdoctoral fellowship for Dr. Jami Gurley). Elliott (Sponsor)
  • NIH R01EY021238: Corneal Lymphatics & Adaptive Immunity. Carr (PI), Elliott (co-I)
  • NIH R01HL132553: Tetraspanin-enriched Microdomains and Endothelial Barrier Function. Zhang (PI), Elliott (co-I)
  • NIH P30 EY021725: Core Grant for Vision Research. Anderson (PI), Elliott (Module director)