CXCR3-Mediated Cell-Cell Communication in Glaucoma

CXCR3 介导的青光眼细胞间通讯

• 批准号: 10539828
• 负责人: Gracie Vargas
• 金额: $ 43.09万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539828
• 关键词: Astrocytes; Attenuated; Autoimmune; Axon; Binding; Blindness; Bone Marrow; C3AR1 gene; CXC chemokine receptor 3; CXCL10 gene; CXCR3 gene; Cardiovascular Diseases; Cell Communication; Cell Death; Cells; Chronic; Clinic; Clinical Trials; Communication; Complement 3; Data; Degenerative Disorder; Disease; Disease Progression; Dominant-Negative Mutation; Family; Functional disorder; Gene Delivery; Glaucoma; Histology; Image; Immune; Immunologic Factors; Immunotherapeutic agent; In Vitro; Infiltration; Inflammation; Inflammatory; Knockout Mice; Knowledge; Leukocyte Trafficking; Leukocytes; Mediating; Membrane; Methodology; Microglia; Microspheres; Modeling; Mus; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neuroglia; Neuronal Injury; Non-Steroidal Anti-Inflammatory Agents; Optic Nerve; Optic Nerve Injuries; Optics; Organism; Pathogenesis; Pathologic; Pathway interactions; Peptides; Phase I Clinical Trials; Physiologic Intraocular Pressure; Play; Reperfusion Therapy; Research; Retina; Retinal Ganglion Cells; Risk Factors; Role; Safety; Series; Signal Transduction; Strategic Planning; System; T-Lymphocyte; Testing; Therapeutic Intervention; Tissues; Up-Regulation; Vision; antagonist; axonal degeneration; base; cell injury; cell type; chemokine; chemokine receptor; conditional knockout; gene therapy; injured; loss of function; macrophage; monocyte; mouse model; neuroprotection; non-invasive imaging; novel; novel therapeutic intervention; optic nerve disorder; prevent; real-time images; receptor; recruit; retinal ganglion cell degeneration; retinal ischemia; targeted treatment; time use; translational potential

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.

CXCR 3介导的青光眼细胞间通讯 总结 青光眼，其特征在于进行性视网膜神经节细胞（RGC）死亡和视神经损害。 退化，是全球不可逆失明的第二大原因。眼内压升高 (IOP)是青光眼的主要危险因素，并且是治疗干预的唯一目标。然而，降低 IOP并不总是阻止疾病进展。有一个未满足的需要，了解机制， 青光眼神经变性和确定青光眼治疗的新靶点。细胞间通讯 在多细胞生物的病理生理变化中起关键作用。趋化因子是一个结构上 相关的促炎肽，在受损/感染细胞之间的通讯中起核心作用 和其它细胞类型通过结合到它们各自靶细胞膜上的特异性趋化因子受体 细胞虽然已经充分认识到趋化因子在肿瘤的发病机制中起关键作用， 炎症、自身免疫、感染、肿瘤、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还很不清楚。CXCL 10是趋化因子， 它的受体是CXCR 3。该通路通过募集和激活几种类型的炎症因子在炎症中起关键作用。 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 CXCL 10/CXCR 3通路在RGCs与其他细胞类型之间的通讯中起重要作用 （免疫细胞和星形胶质细胞），阻断这一途径会导致功能障碍/变性 视网膜神经节细胞及其轴突的结构。我们提出以下三个目标：（目的1）检验CXCR 3 信号传导在RGC和免疫细胞之间的通信中起着关键作用，这有助于 青光眼性视神经病变;（目的2）检验CXCR 3诱导毒性RGC-星形胶质细胞的假设 通过CXCR 3介导的C3/C3 aR信号传导的串扰;（Aim 3）检验阻断CXCR 3是一种干扰的假设。 有效治疗青光眼的方法。我们将在研究中整合一系列新颖的方法，如 骨髓嵌合小鼠，CXCR 3条件性基因敲除小鼠，AAV 2介导的基因治疗，实时荧光定量PCR 白细胞运输成像、组织光学清除和临床相关的非侵入性成像和功能 试验.综上所述，我们提出的研究将提供重要的新知识，CXCL 10/CXCR 3介导的 神经退行性变中的细胞间通讯，并可能确定新的治疗方法来管理 青光眼性视神经病变本提案符合“研究需求、差距和机会” 在NEI战略计划中确定：1）非神经元细胞（如神经胶质细胞）的作用对于理解 退行性疾病; 2）研究挑战正统观念的免疫因子的神经生物学作用， 检查这些“免疫”因素是否在视觉功能中发挥非传统作用; 3）确定目标 用于免疫相关疾病的治疗剂或非甾体抗炎药。