As phagocytes, retinal pigment epithelial cells function as homeostatic regulators to maintain photoreceptor integrity and preserve visual function. Thus it is advantageous for the post-mitotic RPE cell to utilize catabolic pathways that result in degradation of phagocytosed cargo that under stress can handle ingestion of oxidized toxic substrates. We propose that phagosome maturation in the RPE includes LC3 lipidation in an LC3 associated phagocytic (LAP) process. We hypothesize that these processes are critical in RPE lipid homeostasis by providing a docasahexaenoic acid (DHA;22:6) pool for Neuroprotectin D1 (NPD1) synthesis to promote RPE cell survival and in turn sustain photoreceptor integrity.
In specific aim 1 we will test the hypothesis that RPE phagosomes annex components of the autophagy pathway in LAP and assess the contribution of oxidized outer segments (OS) to this process.
In specific aim 2 we hypothesize that melanoregulin (MREG) mediated degradation involves LAP and will determine the role of MREG, an LC3 binding partner, in this process.
In Specific Aim 3, we focus our studies on understanding the protective role of LAP and MREG mediated degradation of OS lipids in maintaining RPE health. These studies will provide the ground-work for understanding how deficiencies in LAP dependent processes contribute to disease progression.

Public Health Relevance

As phagocytes, retinal pigment epithelial cells function as a homeostatic regulator to maintain photoreceptor integrity and preserve visual function. Impairment of photoreceptor clearance contributes to age-related retinopathies characterized by sub-retinal deposits as well as lipofuscinosis ultimately leading to blindness. In these studies we will investigate a novel degradative pathway utilized by the retinal pigment epithelia to digest toxic debris and provide precursors for neuroprotection. This pathway called, LC3 associated phagocytosis (LAP), utilizes components of two different albeit interconnected digestive processes, autophagy and phagocytosis. Critical for degradation by this pathway is the protein melanoregulin (MREG). Understanding how the retinal pigment epithelia recognizes debris to be degraded by LAP and the role of MREG in this process will allow us to develop new therapeutic approaches to enhancing degradation in disease progression.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CB-G (02))
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Neuhold, Lisa
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University of Pennsylvania
Schools of Dentistry
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