CXCR3-Mediated Cell-Cell Communication in Glaucoma

CXCR3介导的青光眼细胞间通讯 摘要 青光眼，其特征是进行性视网膜神经节细胞(RGC)死亡和视神经 退化是全世界第二大不可逆转的致盲原因。眼压升高 眼压(IOP)是青光眼的主要危险因素，也是治疗干预的唯一目标。然而，降低 眼压并不总是能阻止疾病的发展。有一种尚未得到满足的需求，即了解 青光眼的神经退行性变和青光眼治疗的新靶点。细胞间的通讯发挥作用 在多细胞生物体的病理生理变化中起关键作用。趋化因子在结构上是一个家族 相关的促炎性多肽在损伤/感染细胞之间的交流中发挥核心作用 和其他类型的细胞通过与其各自靶细胞膜上的特定趋化因子受体结合 细胞。虽然人们已经很好地认识到趋化因子在肺癌的发病机制中起着关键作用。 炎症性、自身免疫性、感染性、肿瘤性、心血管和神经退行性疾病 视网膜源性趋化因子在青光眼视神经病变中的作用在很大程度上是未知的。CXCL10是一种趋化因子 其受体为CXCR3。这一途径通过招募和激活几种类型的 白细胞包括巨噬细胞/小胶质细胞和T细胞。在这个项目中，我们假设 CXCL10/CXCR3通路在视网膜节细胞与其他类型细胞之间的通讯中起着至关重要的作用 (免疫细胞和星形胶质细胞)在青光眼期间，阻断这一途径可缓解功能障碍/变性 RGC和它们的轴突。我们提出了以下三个目标：(Aim1)检验CXCR3的假设 信号在RGC和免疫细胞之间的通信中起着关键作用，这有助于 青光眼视神经病变；(AIM2)检验CXCR3诱导毒性RGC-星形胶质细胞的假说 通过CXCR3介导的C3/C3aR信号的串扰；(Aim3)检验阻断CXCR3是一种 治疗青光眼的有效方法。我们将在研究中融入一系列新的方法，例如 骨髓嵌合小鼠，CXCR3条件基因敲除小鼠，AAV2介导的基因治疗，实时 白细胞转运、组织光学清除、临床相关的非侵入性成像和功能成像 测试。综上所述，我们拟议的研究将提供关于CXCL10/CXCR3介导的重要新知识 神经退行性变中的细胞-细胞通讯，并可能确定新的治疗方法 青光眼视神经病变。这项建议符合“研究需要、差距和机遇” NEI战略计划中确定：1)神经胶质等非神经细胞的作用对于理解 退行性疾病；2)研究挑战正统和 检查这些“免疫”因素是否对视觉功能起着非传统的作用；3)确定目标 免疫相关疾病的治疗药物或非类固醇消炎药。

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.