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.
This proposal describes basic science research to understand the fundamental cellular functions of two RPE-expressed proteins, LRP2 and MFRP, that when mutated cause a spectrum is ocular pathologies, including myopia or hyperopia, respectively, as well as retinal dystrophies. A common consequence for disruption of either gene is abnormal ECM maintenance and fibrosis, but also activation of the innate immune response and recruitment of macrophages ? each which are hallmarks of most ocular diseases and eye pathogenesis. This proposal, therefore, also address broader questions about how refractive errors such as myopia and hyperopia are significant risk factors for many ocular diseases, including a number of retinal dystrophies such as glaucoma and photoreceptor degeneration.
