RPE Signaling in Ocular Health and Disease

研究综述 这项建议描述了两种跨膜蛋白LRP2的细胞功能的实验 以及MFRP，当在人类和动物模型中发生突变时，会导致一系列眼部疾病， 包括视网膜营养不良和屈光不正。LRP2是低密度脂蛋白的一种大跨膜蛋白 受体相关蛋白(LRP)家族。MFRP也是一种跨膜蛋白，因其C- 末端和胞外富含半胱氨酸的Frizzled域，尽管它也有CUB和LDLA结构域。 在眼内，LRP2和MFRP均在RPE和睫状体上皮细胞上特异表达。穿过 三个具体目的，我们探讨(1)LRP2和MFRP之间潜在的合作功能 接收和传递信号并调节细胞过程(2)它们参与招募和 巨噬细胞在正常眼球生长和病理过程中的激活，以及(3)它们的蛋白结合 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 对RPE细胞的特定信号通路和细胞过程的调节，重点是它们的 眼部小胶质细胞和巨噬细胞在细胞外基质动态平衡中的作用 健康和疾病。总的来说，我们的研究也将有助于理解眼部纤维化和 视网膜病变。

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.