RPE Signaling in Ocular Health and Disease

眼部健康和疾病中的 RPE 信号传导

• 批准号: 10250509
• 负责人: Brian A Link
• 金额: $ 44.01万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250509
• 关键词: Address; Animal Model; Animals; Basic Science; Binding Proteins; Blood Vessels; C-terminal; Cell Lineage; Cell physiology; Cells; Ciliary epithelium; Clinical; Cysteine; Defect; Disease; Epithelial Cells; Extracellular Matrix; Eye; Eye Abnormalities; Fibrosis; Frizzled Domain; Functional disorder; Genes; Glaucoma; Growth; Health; Homeostasis; Hyperopia; Immune response; Inflammation; Innate Immune Response; Integral Membrane Protein; LDL-Receptor Related Proteins; Lead; Link; Macrophage Activation; Maintenance; Microglia; Morphology; Mus; Mutate; Mutation; Myelogenous; Myopia; Names; Nerve Degeneration; Ocular Pathology; Pathogenesis; Pathology; Pathway interactions; Phenotype; Plant Roots; Protein Family; Proteins; Refractive Errors; Regulation; Research; Retina; Retinal Diseases; Retinal Dystrophy; Risk Factors; Role; Sclera; Signal Pathway; Signal Transduction; Signaling Protein; Testing; Zebrafish; experimental study; extracellular; genetic testing; human model; insight; macrophage; mutant; photoreceptor degeneration; recruit

RESEARCH SUMMARY This proposal describes experiments to address cellular functions of two transmembrane proteins, LRP2 and MFRP, that when mutated in humans and animal models cause a spectrum of ocular pathologies, including retinal dystrophies and refractive errors. LRP2 is a large transmembrane protein of the LDL- receptor related protein (LRP) family. MFRP is also a transmembrane protein and was named for its C- terminal and extracellular cysteine rich Frizzled domain, although it also has CUB and LDLA domains. Within eyes, both LRP2 and MFRP are specifically expressed on RPE and ciliary epithelial cells. Through three Specific Aims, we probe (1) the potential functional cooperatively between LRP2 and MFRP in receiving and transducing signals and regulating cellular processes (2) their involvement in recruitment and activation of macrophages in normal eye growth and during pathology, and (3) their protein binding partners and the possibility they interact directly. The proposed research will provide fundamental insights into regulation of specific signaling pathways and cellular processes of RPE cells with emphasis on their role in extracellular matrix homeostasis and in regulation of microglia and macrophages during ocular health and disease. Broadly, our studies will also help understand the links between ocular fibrosis and retinal pathologies.

研究摘要 该建议描述了解决两种跨膜蛋白LRP2的细胞功能的实验 和MFRP，当在人类和动物模型中突变时会引起各种眼科病理， 包括视网膜营养不良和折射率。 LRP2是LDL-的大型跨膜蛋白 受体相关蛋白（LRP）家族。 MFRP也是跨膜蛋白，以其C-的名字命名 末端和细胞外半胱氨酸富含毛茸茸的结构域，尽管它也具有幼崽和LDLA结构域。 在眼睛内，LRP2和MFRP均在RPE和纤毛上皮细胞上特别表达。通过 三个特定目标，我们探测（1）LRP2和MFRP之间的潜在功能 接收和转导信号并调节细胞过程（2）它们参与招募和 巨噬细胞在正常眼生长和病理学期间的激活，以及（3）其蛋白质结合 合作伙伴和他们直接互动的可能性。拟议的研究将提供基本的见解 调节RPE细胞的特定信号通路和细胞过程，重点 眼外基质体内稳态以及眼镜中的小胶质细胞和巨噬细胞的作用 健康与疾病。从广义上讲，我们的研究还将有助于了解眼纤维化与 视网膜病理。