Photoreceptor death underlies many types of retinal degeneration, including age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Our long-term goal is to understand mechanisms of photoreceptor survival. During retinal injury, Muller glia cells play a protective role by secreting pro-survival growth factors to protect remaining photoreceptors in a toxic environment. The signaling pathways that lead to growth factor induction are largely unknown. Therefore, elucidating the molecular mechanisms that regulate growth factor induction will be important for understanding the potential therapeutic properties of these important molecules and for identifying novel, more effective, treatments. The Wnt pathway is an essential signaling cascade that mediates retinal development and retinal stem cell proliferation and is a critical regulator of cell survival in degenerative conditions of the brain, such as Alzheimers disease. Several lines of evidence suggest that Wnt signaling is protective in the retina and that it may induce growth factors from Muller glia or act directly on photoreceptors. Our hypothesis is that Wnt signaling plays a pro-survival role during retinal degeneration. In this study we will delineate the role of Wnt signaling in the Muller glia- growth factor injury response using primary Muller glia cultures (Aim 1). To identify the role of Wnt signaling during retinal degeneration we will use viral vectors to over-express Wnt activators and inhibitors in primary retinal cultures and in vivo (Aims 2 and 3). Together, these experiments will advance our understanding of pathways regulating photoreceptor survival and will identify a new cellular signaling mechanism linking photoreceptors and Muller glia. Furthermore, the results from this study will demonstrate whether modifying the Wnt pathway can be used as a therapeutic strategy for retinal degenerations.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY017837-04
Application #
7879933
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
2007-08-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$340,808
Indirect Cost
Name
University of Miami School of Medicine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Patel, Amit K; Akinsoji, Elizabeth; Hackam, Abigail S (2016) Defining the Relationships Among Retinal Function, Layer Thickness and Visual Behavior During Oxidative Stress-Induced Retinal Degeneration. Curr Eye Res 41:977-86
Patel, Amit K; Surapaneni, Krishna; Yi, Hyun et al. (2015) Activation of Wnt/?-catenin signaling in Muller glia protects photoreceptors in a mouse model of inherited retinal degeneration. Neuropharmacology 91:1-12
Patel, Amit K; Hackam, Abigail S (2014) A novel protective role for the innate immunity Toll-Like Receptor 3 (TLR3) in the retina via Stat3. Mol Cell Neurosci 63:38-48
Patel, Amit K; Hackam, Abigail S (2013) Toll-like receptor 3 (TLR3) protects retinal pigmented epithelium (RPE) cells from oxidative stress through a STAT3-dependent mechanism. Mol Immunol 54:122-31
Yi, Hyun; Hu, Jianfei; Qian, Jiang et al. (2012) Expression of brain-derived neurotrophic factor is regulated by the Wnt signaling pathway. Neuroreport 23:189-94
Fragoso, Miryam A; Patel, Amit K; Nakamura, Rei E I et al. (2012) The Wnt/?-catenin pathway cross-talks with STAT3 signaling to regulate survival of retinal pigment epithelium cells. PLoS One 7:e46892
Yi, Hyun; Patel, Amit K; Sodhi, Chhinder P et al. (2012) Novel role for the innate immune receptor Toll-like receptor 4 (TLR4) in the regulation of the Wnt signaling pathway and photoreceptor apoptosis. PLoS One 7:e36560
Fragoso, Miryam A; Yi, Hyun; Nakamura, Rei E I et al. (2011) The Wnt signaling pathway protects retinal ganglion cell 5 (RGC-5) cells from elevated pressure. Cell Mol Neurobiol 31:163-73
Nakamura, Rei E I; Hackam, Abigail S (2010) Analysis of Dickkopf3 interactions with Wnt signaling receptors. Growth Factors 28:232-42
Silva, Amanda K; Yi, Hyun; Hayes, Sarah H et al. (2010) Lithium chloride regulates the proliferation of stem-like cells in retinoblastoma cell lines: a potential role for the canonical Wnt signaling pathway. Mol Vis 16:36-45

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