Project Grant R21EY035843

A NOVEL MOUSE MODEL FOR SPONTANEOUS AND AGE-RELATED CHOROIDAL NEOVASCULARIZATION - ABSTRACT CHOROIDAL CAPILLARIES ARE NORMALLY KEPT BEHIND THE RETINA BY THE RETINAL PIGMENT EPITHELIUM (RPE), A MONOLAYER OF CELLS LOCATED BETWEEN THE RETINAL PARENCHYMA AND CHOROIDAL PLEXUS. IN HUMANS, RPE INTEGRITY MAY DETERIORATE WITH AGING, ESPECIALLY IN A SMALL CENTRAL AREA OF THE RETINA KNOWN AS THE MACULA. AS A RESULT, THE NORMALLY AVASCULAR PHOTORECEPTOR TISSUE MAY BECOME INVADED BY LEAKY CHOROIDAL CAPILLARIES THROUGH CHOROIDAL NEOVASCULARIZATION (CNV), WHICH IS A HALLMARK OF THE WET FORM OF AGE-RELATED MACULAR DEGENERATION (AMD) AND A LEADING CAUSE OF BLINDNESS AMONG THE SENIOR POPULATION. DESPITE THE SHORT-TERM BENEFITS OF ANTI-VEGF THERAPY, THERE IS STILL NO EFFECTIVE LONG-TERM TREATMENT. TO PROMOTE THE DEVELOPMENT OF NOVEL THERAPIES WITH LONG-TERM BENEFITS, WE PROPOSE TO CREATE A CHRONIC CNV MODEL IN WHICH CNV OCCURS DUE TO A SET OF PATHOPHYSIOLOGICAL CONDITIONS MIMICKING THOSE ASSOCIATED WITH WET AMD, INCLUDING GENETIC SUSCEPTIBILITY, STRESSFUL ENVIRONMENT, AND AGING. WE WILL REFER TO THE NOVEL MOUSE MODEL AS AGE-RELATED CNV (ARCNV), FOLLOWING THE STYLE OF "AGE-RELATED MACULAR DEGENERATION", ALTHOUGH AGING IS NOT THE ONLY TRIGGER IN BOTH CASES. IN PRELIMINARY STUDIES, GENETIC SUSCEPTIBILITY WAS INTRODUCED INTO MICE BY THE KNOCKIN OF A CRE-DEPENDENT TRANSGENE THAT IS DESIGNED TO KNOCK DOWN 5 SPECIFIC MRNA TARGETS (THROUGH THE EXPRESSION OF 5 SIRNAS) AND OVEREXPRESS TWO PROTEINS. THE CANDIDATE GENES WERE SELECTED BECAUSE THEIR HUMAN HOMOLOGS ARE ASSOCIATED WITH INCREASED RISK OF WET AMD. TO SIMULATE ENVIRONMENTAL RISKS, WE DESIGNED A NOVEL TREATMENT REGIME CONSISTING OF OXIDATIVE DIET, SMOKING PRODUCT, AND LIGHT (OXDSL). WHEN CARRIED OUT SEPARATELY, CRE-ACTIVATION OF THE TRANSGENE OR TREATMENT OF WILD-TYPE C57BL/6J MICE WITH OXDSL ALONE LED TO PRE-CNV PHENOTYPES SUCH AS RPE DEGENERATION, BUT NOT OUTRIGHT CNV. IN COMBINATION, HOWEVER, GLOBAL TRANSGENE ACTIVATION AND TREATMENT WITH OXDSL LED TO CNV BY 7 MONTHS OF AGE, BUT NOT AT MUCH YOUNGER AGES. THUS, THE ARCNV MODEL IS AGE- DEPENDENT. ON OTHER HAND, THE OCCURRENCE OF CNV AT THE RELATIVELY EARLY PHASE OF AGING WILL ACCELERATE RESEARCH PROGRESS. IN PROPOSED STUDIES, WE WILL SYSTEMATICALLY CHARACTERIZE CNV ONSET AND PROGRESSION, ALONG WITH RELATED PHENOTYPES AND MOLECULAR CHANGES (AIM 1). GIVEN THE CENTRAL ROLE OF THE RPE BARRIER, WE WILL ALSO ACTIVATE THE TRANSGENE WITH RPE-SPECIFIC CRE AND INVESTIGATE WHETHER SUCH MICE WILL DEVELOP CNV WHEN TREATED WITH THE OXDSL REGIME (AIM 2). AT THE COMPLETION OF THIS PROJECT, WE WILL HAVE SYSTEMATICALLY CHARACTERIZED THIS NOVEL MOUSE MODEL, THUS PROVIDING A HIGHLY VALUABLE TOOL TO THE CNV RESEARCH COMMUNITY.