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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Shen, Grace L
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Johns Hopkins University
Schools of Medicine
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Cano, Marisol; Wang, Lei; Wan, Jun et al. (2014) Oxidative stress induces mitochondrial dysfunction and a protective unfolded protein response in RPE cells. Free Radic Biol Med 69:1-14
Chen, Chen; Cano, Marisol; Wang, Joshua J et al. (2014) Role of unfolded protein response dysregulation in oxidative injury of retinal pigment epithelial cells. Antioxid Redox Signal 20:2091-106
Wang, Lei; Cano, Marisol; Handa, James T (2014) p62 provides dual cytoprotection against oxidative stress in the retinal pigment epithelium. Biochim Biophys Acta 1843:1248-58
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
Ebrahimi, Katayoon B; Fijalkowski, Natalia; Cano, Marisol et al. (2014) Oxidized low-density-lipoprotein-induced injury in retinal pigment epithelium alters expression of the membrane complement regulatory factors CD46 and CD59 through exosomal and apoptotic bleb release. Adv Exp Med Biol 801:259-65
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Sachdeva, Mira M; Cano, Marisol; Handa, James T (2014) Nrf2 signaling is impaired in the aging RPE given an oxidative insult. Exp Eye Res 119:111-4
Barnett, Brad P; Handa, James T (2013) Retinal microenvironment imbalance in dry age-related macular degeneration: a mini-review. Gerontology 59:297-306

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