Age-related macular degeneration (AMD) is the leading cause of acquired blindness in the United States. Patients with early disease suffer from limited and ineffective options for prevention and treatment. To address this shortcoming, this proposal focuses on the mechanisms underlying early disease. Cigarette smoking is the strongest epidemiological link with AMD, yet we do not fully understand its role in the pathophysiology of this disease. Cigarette smoke is a powerful chemical oxidant, and a potent inducer of complement activation. Both of these factors are thought to be important in AMD development. A key early event in AMD is apoptosis of the retinal pigmented epithelium (RPE), in part through inadequately neutralized oxidative stress. Nuclear factor- erythroid 2-related factor 2 (Nrf2), a basic leucine zipper redox-sensitive transcription factor, regulates the inducible expression of antioxidant and cytoprotective genes by binding to the cis-acting enhancer sequence known as the antioxidant response element. Normally, Nrf2 levels are low, but with an oxidative stimulus, nuclear accumulation of Nrf2 increases after it is released from its cytoplasmic inhibitor Keap1, and activates the coordinated transcription of its downstream antioxidant enzymes. Decreased Nrf2 signaling is seen in aging and disease, resulting in an inadequate adaptive stress response. Intriguingly, the decreased Nrf2 activity can be reversed by the synthetic triterpenoid derivatives of oleonolic acid, which represent a promising new class of agents for cytoprotection from oxidative injury. In this proposal, we hypothesize that chronic cigarette smoking induces persistent oxidative stress in the fundus, and that local Nrf2 signaling becomes inadequate with the onset of AMD. Recently, we showed that chronic cigarette smoke induces oxidative and ultrastructural damage, and eventually apoptosis to the RPE of mice. We will exploit this system using genetically modified mice to address our hypothesis with the following aims: 1) To test the hypothesis that Nrf2 signaling protects against cigarette smoke-induced oxidative stress and apoptosis in the fundus. 2) To investigate the hypothesis that regulation by Nrf2 signaling on complement activation determines the damage and apoptosis to the fundus that is induced by cigarette smoke. 3) To determine if a pharmacological activator of Nrf2 protects the fundus from oxidative damage and complement activation.
Age-related macular degeneration is now the most common cause of blindness among the elderly in the United States, yet our understanding of how early disease develops is limited. Cigarette smoking is the strongest risk factor associated with AMD yet we do not understand how it causes disease onset or progression. This proposal will study how cigarette smoking triggers the onset of macular degeneration. Experiments will explore if Nuclear factor-erythroid 2-related factor 2 (Nrf2), a transcription factor that activates antioxidant and cytoprotective enzymes, protects against cigarette smoke induced oxidative stress and complement activation. This proposal will also explore whether triterpenoids, or small molecules that can activate Nrf2, will prevent the development of AMD in mouse models.
|Shang, Peng; Valapala, Mallika; Grebe, Rhonda et al. (2017) The amino acid transporter SLC36A4 regulates the amino acid pool in retinal pigmented epithelial cells and mediates the mechanistic target of rapamycin, complex 1 signaling. Aging Cell 16:349-359|
|Datta, Sayantan; Cano, Marisol; Ebrahimi, Katayoon et al. (2017) The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD. Prog Retin Eye Res 60:201-218|
|Wei, Hong; Xun, Zixian; Granado, Herta et al. (2016) An easy, rapid method to isolate RPE cell protein from the mouse eye. Exp Eye Res 145:450-455|
|Sinha, Debasish; Valapala, Mallika; Shang, Peng et al. (2016) Lysosomes: Regulators of autophagy in the retinal pigmented epithelium. Exp Eye Res 144:46-53|
|Wang, Lei; Ebrahimi, Katayoon B; Chyn, Michelle et al. (2016) Biology of p62/sequestosome-1 in Age-Related Macular Degeneration (AMD). Adv Exp Med Biol 854:17-22|
|Wang, Lei; Cano, Marisol; Datta, Sayantan et al. (2016) Pentraxin 3 recruits complement factor H to protect against oxidative stress-induced complement and inflammasome overactivation. J Pathol 240:495-506|
|Handa, James T; Tagami, Mizuki; Ebrahimi, Katayoon et al. (2015) Lipoprotein(A) with An Intact Lysine Binding Site Protects the Retina From an Age-Related Macular Degeneration Phenotype in Mice (An American Ophthalmological Society Thesis). Trans Am Ophthalmol Soc 113:T5|
|Valapala, Mallika; Wilson, Christine; Hose, Stacey et al. (2014) Lysosomal-mediated waste clearance in retinal pigment epithelial cells is regulated by CRYBA1/?A3/A1-crystallin via V-ATPase-MTORC1 signaling. Autophagy 10:480-96|
|Wang, Lei; Kondo, Naoshi; Cano, Marisol et al. (2014) Nrf2 signaling modulates cigarette smoke-induced complement activation in retinal pigmented epithelial cells. Free Radic Biol Med 70:155-66|
|Cruz-Guilloty, Fernando; Saeed, Ali M; Duffort, Stephanie et al. (2014) T cells and macrophages responding to oxidative damage cooperate in pathogenesis of a mouse model of age-related macular degeneration. PLoS One 9:e88201|
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