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Degradative Processes in RPE-photoreceptor renewal

RPE 光感受器更新的降解过程

基本信息

批准号：
8798656
负责人：
Kathleen Boesze-Battaglia
金额：
$ 45.77万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/8798656
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 response

项目摘要

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作为稳态调节剂发挥作用，以维持感光细胞的完整性并保护视觉功能。因此，有丝分裂后RPE细胞利用分解代谢途径是有利的，所述分解代谢途径导致在应激下可以处理氧化的毒性底物的摄取的被吞噬的货物的降解。我们认为RPE中的吞噬体成熟包括LC 3相关吞噬细胞（LC 3）过程中的LC 3脂化。我们假设，这些过程是至关重要的RPE脂质稳态提供了一个二十二碳六烯酸（DHA; 22：6）池神经保护素D1（NPD 1）的合成，以促进RPE细胞的存活，并反过来维持感光细胞的完整性。在具体目标1中，我们将检验RPE吞噬体在视网膜中附件自噬途径组分的假设，并评估氧化外节（OS）对该过程的贡献。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LC 3，并将确定MREG（LC 3结合伴侣）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RPEs和MREG介导的OS脂质降解在维持RPE健康中的保护作用。这些研究将为理解依赖性过程的缺陷如何导致疾病进展提供基础。