Degradative Processes in RPE-photoreceptor renewal

RPE 光感受器更新的降解过程

• 批准号: 8648882
• 负责人: Kathleen Boesze-Battaglia
• 金额: $ 48.21万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8648882
• 关键词: Acids; Autophagocytosis; Autophagosome; Binding; Biological Assay; Blindness; Cathepsins; Cell Death; Cell Survival; Cell physiology; Cells; Data; Degradation Pathway; Deposition; Digestion; Disease Progression; Docosahexaenoic Acids; Ensure; Event; Felis catus; Genes; Goals; Health; Homeostasis; Hybrids; Impairment; In Vitro; Ingestion; Light; Lipids; Lysosomes; MAP1 Microtubule-Associated Protein; Maintenance; Malondialdehyde; Mediating; Mitotic; Molecular; Mus; Opsin; Oxidative Stress; Pathway interactions; Phagocytes; Phagocytosis; Phagosomes; Phospholipase A2; Phospholipids; Photoreceptors; Process; Property; Proteins; Recruitment Activity; Research; Retina; Retinal; Retinal Diseases; Role; Series; Sorting - Cell Movement; Stress; Structure of retinal pigment epithelium; Testing; Up-Regulation; Vision; Work; age related; base; hydroxy-aluminum polymer; in vitro Model; in vivo; neuroprotectin D1; neuroprotection; novel; novel therapeutic intervention; public health relevance; response

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：作为吞噬细胞，视网膜色素上皮细胞起到稳态调节剂的作用，以维持光感受器的完整性并保护视觉功能。因此，对于有丝分裂后的 RPE 细胞来说，利用导致吞噬货物降解的分解代谢途径是有利的，而吞噬货物在应激下可以处理氧化有毒底物的摄入。我们认为 RPE 中的吞噬体成熟包括 LC3 相关吞噬 (LAP) 过程中的 LC3 脂化。我们假设这些过程对于 RPE 脂质稳态至关重要，为神经保护素 D1 (NPD1) 合成提供二十二碳六烯酸 (DHA; 22:6) 库，以促进 RPE 细胞存活，进而维持感光体完整性。在具体目标 1 中，我们将测试 RPE 吞噬体吞并 LAP 中自噬途径成分的假设，并评估氧化外段 (OS) 对此过程的贡献。在具体目标 2 中，我们假设黑素调节蛋白 (MREG) 介导的降解涉及 LAP，并将决定 LC3 结合伴侣 MREG 在此过程中的作用。在具体目标 3 中，我们的研究重点是了解 LAP 和 MREG 介导的 OS 脂质降解在维持 RPE 健康方面的保护作用。这些研究将为理解 LAP 依赖性过程的缺陷如何导致疾病进展奠定基础。