Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly, yet patients with early disease are without therapy. To address this shortcoming, this proposal focuses on early disease. Two key events in early AMD are retinal pigment epithelial cell (RPE) dysfunction and drusen biogenesis. Inadequately neutralized reactive oxygen species (ROS) and dysregulated innate immunity interact together to play a pivotal role. Central to oxidative homeostasis, especially in mitochondria, is the Nrf2 transcription factor, which controls the most comprehensive antioxidant response system. Nrf2 signaling can become impaired with aging and/or smoking. The objective of this proposal to define how Nrf2 protects against RPE mitochondrial dysfunction and unregulated innate immunity. The hypothesis to be tested is that that impaired Nrf2 signaling induces mitochondrial and RPE dysfunction that results in an oxidative, inflammatory, and pathologic microenvironment. The proposed specific aims are: 1. Determine the extent that impaired Nrf2 signaling leads to un-neutralized mitochondrial ROS and RPE dysfunction with cigarette smoke exposure. Our hypothesis is that impaired Nrf2 signaling in the RPE from aging and chronic smoking reduces mitochondrial antioxidant defense resulting in inadequately neutralized ROS and RPE dysfunction. 2. Determine the extent that impaired Nrf2 signaling decreases mitophagy, and results in RPE dysfunction with cigarette smoke exposure. Our hypothesis is that impaired Nrf2 signaling in the RPE from aging and chronic smoking decreases mitophagy, cumulatively increasing the number of dysfunctional mitochondria and inadequately neutralized ROS, resulting in RPE dysfunction. 3. Determine the extent that impaired Nrf2 signaling disrupts regulation of innate immunity. Based on our work showing C3a and IL-1b generation by CS and Nrf2 deficiency, our hypothesis is that impaired Nrf2 signaling magnifies oxidative stress, which activates the inflammasome to promote a pro-inflammatory microenvironment with accumulation of macrophages with impaired function. These contributions are significant because they will establish Nrf2 as a treatment target for early AMD. The research is innovative since it will investigate understudied (decreased Nrf2 signaling on mitochondrial antioxidants and mitophagy), unresolved (inflammasome and macrophage function) and unique (the synergy of ROS and innate immunity) factors on RPE and macrophage function using unique, state-of-the- art genetic mice with fresh, but decisive factors that have not been previously tested. Macrophages will be studied from a new perspective that defines both phenotype and function since both are influenced by their surroundings. Our discovery of reduced Nrf2 with aging and CS, which generates C3a and IL-1b, a key substrate of the inflammasome, and the proposed studies, which will link complement with the inflammasome, macrophage function, and an AMD phenotype, is highly innovative. Targeted therapy that reinvigorates Nrf2 to maintain oxidative homeostasis and protective innate immunity is expected to result from this work.
Age-related macular degeneration (AMD), the most common cause of blindness among the elderly, is triggered by oxidative stress, which imbalances innate immunity. Retinal pigment epithelial (RPE) cell damage is a key event in early disease that is regulated by the transcription factor Nrf2, which controls the cell's most comprehensive known antioxidant system. This proposal will study how aging and oxidative stress impair Nrf2, which increases oxidative stress through mitochondrial damage, and the development of RPE damage, deregulation of innate immunity, and development of early AMD.
|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|
Showing the most recent 10 out of 36 publications