User:Wan Jin Jahng

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Retina Proteomics Laboratory


We have focused on understanding the cell death mechanism of the retina and RPE under oxidative stress [Chung et al., 2009; Lee et al., 2010a; Lee et al., 2010b; Zhang et al., 2010; Lee et al., 2011; Arnouk et al., 2011; Sripathi et al., 2011; Sripathi et al., 2012; Jahng 2012]. Our studies demonstrated that oxidative stress may trigger induction of anti-apoptotic erythropoietin, JAK2, and BCL-xL, as well as pro-apoptotic caspases. Oxidative stress also influences mitochondrial-nuclear communication by shuttling mitochondrial prohibitin. We examined whether phosphorylations of cytoskeletal and anti-apoptotic proteins, including vimentin, PP2A, and crystalline, regulate the initial protecting mechanism. The cytoskeletal network formed by filamentous proteins determines how retinal and RPE cells respond to their extracellular environmental stimuli that include oxidative stress.


While the end point of apoptosis is well established, there is still a large gap between knowledge of early biochemical events and the end stage of age-related macular degeneration (AMD). Proteome changes under oxidative stress have been studied in regard to the pathogenesis of AMD [Yang et al 2006]. Understanding the molecular mechanism of proteomic signaling will provide a novel insight into apoptotic processes in AMD. It is expected that the knowledge will be equally applicable for understanding the lipid-mediated cell death mechanism.


Light-induced retinal degeneration in animal model occurs only when the visual cycle is functional. Regeneration of 11-cis-retinal as a chromophore of rhodopsin is depending on biochemical reactions of retinoid processing enzymes, including lecithin retinol acyltransferase and RPE65 [Xue et al., 2004; Xue et al., 2006; Jahng et al., 2003a; Jahng et al., 2003b; Jahng et al., 2002; Bok et al., 2003]. Activity and expressions of these enzymes might be controlled by circadian regulators or daily light onset [Xue et al., 2004; Chung et al., 2009; Lee et al., 2010a]. A study of RPE65 knockout mice exhibited that light damage only occurs when the retina is supplied with 11-cis retinal [Wenzel et al., 2005]. Additional evidence in RPE65 L450M mice showing slow rhodopsin regeneration, halothane anesthesia as inhibition method of 11-cis-retinal regeneration, and 13-cis-retinoic acid as a putative RPE65 inhibitor imply that continuous regeneration of 11-cis-retinal is one of the key steps to induce retina degeneration [Wenzel et al., 2005].


Our goal is to explicate the role of light and time under oxidative stress in the control of neuroprotective protein expressions in the retina and the RPE [Zimmermann et al., 2006]. Our questions include whether antiapoptotic factors, that include prohibitin, nitric oxide, vimentin, PP2A, and erythropoietin can protect retina and RPE cells against oxidative- or light-induced apoptotic neurodegeneration at specific time points.


Our proteomic approaches to understand RPE cell death under stress conditions demonstrate that: 1) crystallins are upregulated and hyperphosphorylated. 2) neuroprotective erythropoietin and subsequent JAK2 phosphorylations are tightly linked to a specific time after oxidative stress and in anticipation of daily light onset. 3) early signaling molecules, including mitochondrial prohibitin, changes their expression, subcellular localization, phosphorylation, and lipid interaction under oxidative stress. 4) relative lipid compositions, including phosphatidylcholine and cholesterol, are altered under oxidative stress. 5) oxidative stress leads to cytoskeletal reorganization through site-specific vimentin phosphorylations that regulate intermediate filaments, resulting in nonfilamentous particles.


AMD is characterized in its early stages by the presence of extracellular deposits, known as drusen, that accumulates between the basal surface of the RPE and Bruch’s membrane. During the past decade, compelling evidence has emerged implicating the immune system and the complement system in particular in drusen biogenesis and AMD. A number of the proteins detected in drusen are either complement components or related molecules. Despite these significant advances, the identity of the molecules responsible for triggering activation of the complement cascade, as well as the downstream molecular interactions that promote AMD pathology, remain elusive. Our proteomics studies will provide new insight into the underlying mechanisms involved in the development and progression of AMD and further elucidate the relationship between various risk facotors, including oxidative stress and complemnt activation. Such information are critical for the development of more effective therapeutic strategies for the treatment of retinal degeneration that includes AMD.

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