Age-related macular degeneration (AMD) is a slowly progressing multifactorial disease involving genetic ab- normalities and environmental insults. AMD is the leading cause of blindness for Americans over age sixty. As the population ages, the prevalence of AMD will continue to grow, reaching a maximum risk rate of ~30% at age 75. Since smoking significantly increases the risk of AMD and there is a 20% higher incidence of smoking in veterans than in the general U.S. adult civilian population, the VA system will have to provide care for poten- tially up to 7 million or more AMD cases. Current available treatments focus on the late stage of the disease (choroidal neovascularization;CNV);however, those come with significant risks and only target subpopulations of AMD patients. No treatment is available for early AMD (i>85% of all cases). Thus it is paramount that we learn on how to detect AMD early and develop treatments that allow for early disease prevention. While me- chanistic studies have shown that inflammation and smoking are fundamental components of both forms of AMD, genetic studies have demonstrated that polymorphisms in different complement proteins each increase the risk for developing AMD. One of the most detrimental mutations occurs in factor H (fH) an essential inhibi- tor in the complement cascade (fH risk haplotype). Overall, it has been hypothesized that inadequate control of complement-driven inflammation may be a major factor in disease pathogenesis in AMD. Here we wish to an- swer two essential questions: 1) do smoking and complement act synergistically in the disease process;and 2) can we target the complement cascade therapeutically in smoking-related pathology. For this proposal we will be guided by our overall hypothesis that pathologic activation of the AP has direct effects on the RPE, generat- ing a permissive cellular environment for AMD pathology.
Aim 1 is aimed at determining the smoke-induced complement activation pathway in RPE monolayers.
In Aim 2, we will test examine complement levels in se- rum of subjects, correlating levels with haplotype and disease. And finally, our hypothesis will be put to test in vivo in Aim 3. We will use a complement inhibitory strategy using a targeted inhibitor that blocks the alternative complement cascade to interfere with CNV and smoke-induced pathology. Testing the alternative pathway in- hibitor will not only establish its therapeutic value, but in addition, elucidating its mechanisms in animal models will investigate the roles and contributions of the alternative pathway of complement in AMD pathology. Taken together, the objective of the current Merit Review proposal is to further characterize the interaction between complement activation and smoking;whereas the long-term goal is to develop a new treatment to reduce the number of AMD cases and improve veteran care and quality of life. Following the successful completion of the experiments described here we would want to initiate follow-up studies in larger animal models of AMD, ex- plore the pharmacokinetics and toxicology of the compound, to ultimately be prepared to proceed to human clinical trials.
Risk factors for age-related macular degeneration (AMD) involve single nucleotide polymorphisms in the alternative pathway (AP) of complement inhibitor factor H, as well as smoking. Using serum samples of AMD patients and controls we will test the hypothesis that smoking increases AMD risk by increasing complement activation, and that this is positively correlated with factor H SNPs. Animal models of AMD and retinal pigment epithelial cells (RPE) monolayers will be used to identify complement activation at the cellular level due to smoking, and test a complement inhibitor as a possible therapeutic agent for the treatment of AMD.
|Schnabolk, Gloriane; Parsons, Nathaniel; Obert, Elisabeth et al. (2018) Delivery of CR2-fH Using AAV Vector Therapy as Treatment Strategy in the Mouse Model of Choroidal Neovascularization. Mol Ther Methods Clin Dev 9:1-11|
|Shah, Navjot; Ishii, Masakii; Brandon, Carlene et al. (2018) Extracellular vesicle-mediated long-range communication in stressed retinal pigment epithelial cell monolayers. Biochim Biophys Acta Mol Basis Dis 1864:2610-2622|
|Obert, Elisabeth; Strauss, Randy; Brandon, Carlene et al. (2017) Targeting the tight junction protein, zonula occludens-1, with the connexin43 mimetic peptide, ?CT1, reduces VEGF-dependent RPE pathophysiology. J Mol Med (Berl) 95:535-552|
|Bowers, Jacob S; Nelson, Michelle H; Majchrzak, Kinga et al. (2017) Th17 cells are refractory to senescence and retain robust antitumor activity after long-term ex vivo expansion. JCI Insight 2:e90772|
|Shi, Yi; Obert, Elisabeth; Rahman, Bushra et al. (2017) The Retinol Binding Protein Receptor 2 (Rbpr2) is required for Photoreceptor Outer Segment Morphogenesis and Visual Function in Zebrafish. Sci Rep 7:16207|
|Busch, Catharina; Annamalai, Balasubramaniam; Abdusalamova, Khava et al. (2017) Anaphylatoxins Activate Ca2+, Akt/PI3-Kinase, and FOXO1/FoxP3 in the Retinal Pigment Epithelium. Front Immunol 8:703|
|Ishii, Masaaki; Rohrer, Bärbel (2017) Bystander effects elicited by single-cell photo-oxidative blue-light stimulation in retinal pigment epithelium cell networks. Cell Death Discov 3:16071|
|Schnabolk, Gloriane; Beon, Mee Keong; Tomlinson, Stephen et al. (2017) New Insights on Complement Inhibitor CD59 in Mouse Laser-Induced Choroidal Neovascularization: Mislocalization After Injury and Targeted Delivery for Protein Replacement. J Ocul Pharmacol Ther 33:400-411|
|Lobo, Glenn P; Fulmer, Diana; Guo, Lilong et al. (2017) The exocyst is required for photoreceptor ciliogenesis and retinal development. J Biol Chem 292:14814-14826|
|Smith, Amena W; Rohrer, Baerbel; Wheless, Lee et al. (2016) Calpain inhibition reduces structural and functional impairment of retinal ganglion cells in experimental optic neuritis. J Neurochem 139:270-284|
Showing the most recent 10 out of 30 publications