The applicant seeks a K08-Mentored Clinical Scientist Development Award through the NIH-National Eye Institute to support training as an ocular immunologist. Uveitis is responsible for 10% of the legal blindness in the USA. The candidate's long-term aim is to develop novel therapies for uveitis which are more effective and safer than those currently available. To facilitate this goal, better understanding of the patho-physiological processes leading to uveitis is required. The training plan proposed is based on the Cellular and Molecular Biology Graduate Program of the University of Alabama at Birmingham, one of the nation's leading research institutes. The sponsor is a widely recognized expert in the role of complement in autoimmune disease. Upon completion, this training plan will result in the candidate earning a Ph.D. in Cellular & Molecular Biology through the Department of Microbiology. The research plan proposed is as follows. Experimental autoimmune uveitis (EAU) is an animal model for endogenous human posterior uveitis. Work in EAU has shown the importance of organ specific T-cell mediated autoimmunity, but despite this knowledge, understanding of the processes leading to the initiation and potentiation of autoimmune uveitis is lacking. In other T -cell mediated autoimmune diseases a role for the complement system, and a beneficial effect from targeted complement inhibition, has been demonstrated. A role for complement has also been suggested in human and animal uveitis. Prior studies were limited by the inability to target specific aspects of the complement system. Our preliminary data demonstrates a markedly decreased incidence of EAU in mice with astrocyte-targeted expression of the transgene product soluble complement receptor-related protein y, a secreted murine complement activation inhibitor. Based on this preliminary data, the candidate proposes the HYPOTHESIS that complement activation is involved in EAU and inhibition of complement activation reduces the incidence and severity of disease.
SPECIFIC AIMS to be tested include 1) Comparison of the kinetics, incidence, severity and cellular infiltrate in disease between sCrry transgenic and wild-type mice in actively immunized EAU; 2) Determination of protection from disease in adoptively transferred EAU; 3) Determination of whether cytokine/chemokine-mediated effector mechanisms are prevented by astrocyte-targeted sCrry production.
| Read, Russell W; Vogt, Susan D; Barnum, Scott R (2013) The complement anaphylatoxin receptors are not required for the development of experimental autoimmune uveitis. J Neuroimmunol 264:127-9 |
| Vogt, Susan D; Barnum, Scott R; Curcio, Christine A et al. (2006) Distribution of complement anaphylatoxin receptors and membrane-bound regulators in normal human retina. Exp Eye Res 83:834-40 |
| Read, Russell W; Szalai, Alexander J; Vogt, Susan D et al. (2006) Genetic deficiency of C3 as well as CNS-targeted expression of the complement inhibitor sCrry ameliorates experimental autoimmune uveoretinitis. Exp Eye Res 82:389-94 |
