CXCR3-Mediated Cell-Cell Communication in Glaucoma

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CXCR3-mediated Cell-Cell Communication in Glaucoma SUMMARY Glaucoma, which is characterized as progressive retinal ganglion cell (RGC) death and optic nerve degeneration, is the second leading cause of irreversible blindness worldwide. Increased intraocular pressure (IOP) is a main risk factor for glaucoma and is the only target for therapeutic intervention. However, lowering IOP does not always stop the disease progression. There is an unmet need to understand the mechanisms of neurodegeneration in glaucoma and identify novel targets for glaucoma therapy. Cell-cell communication plays a key role in pathophysiological changes in multicellular organisms. Chemokines are a family of structurally related pro-inflammatory peptides that plays a central role in the communication between injured/infected cells and other cell types via binding to specific chemokine receptors on the membrane of their respective target cells. While it has been well appreciated that chemokines are critically involved in the pathogenesis of inflammatory, autoimmune, infectious, oncologic, cardiovascular and neurodegenerative diseases, the role of retina-derived chemokines in glaucomatous optic neuropathy is largely unknown. CXCL10 is a chemokine and its receptor is CXCR3. This pathway has a key role in inflammation by recruiting and activating several types of leukocytes including macrophage/microglia and T cells. In this project, we hypothesize that the CXCL10/CXCR3 pathway has an essential role in the communication between RGCs and other cell types (immune cells and astrocytes) during glaucoma and blocking this pathway alleviates dysfunction/degeneration of RGCs and their axons. We propose the following three aims: (Aim1) Test the hypothesis that CXCR3 signaling plays a key role in the communication between RGCs and immune cells, which contributes to glaucomatous optic neuropathy; (Aim2) Test the hypothesis that CXCR3 induces toxic RGC-astrocyte crosstalk via CXCR3-mediated C3/C3aR signaling; (Aim3) Test the hypothesis that blocking CXCR3 is an effective approach to treat glaucoma. We will integrate a series of novel methodologies in the studies, such as bone marrow chimeric mice, CXCR3 conditional knockout mice, AAV2-mediated gene therapy, real-time imaging of leukocyte trafficking, tissue optical clearing, and clinic-relevant non-invasive imaging and functional tests. Taken together, our proposed study will provide important new knowledge on CXCL10/CXCR3-mediated cell-cell communication in neurodegeneration and may identify the novel therapeutic approaches to manage glaucomatous optic neuropathy. This proposal is in line with “Research Needs, Gaps, and Opportunities” identified in the NEI Strategic Plan: 1) The role of non-neuronal cells such as glia is critical for understanding degenerative diseases; 2) Investigate neurobiology roles for immune factors that challenge orthodoxy and examine whether these “immune” factors are playing nontraditional roles for vision function; 3) Identify targeted therapeutics or non-steroidal anti-inflammatory drugs for immune-related diseases.