Immune Responses in Neuronal Cell Death

神经细胞死亡中的免疫反应

• 批准号: 9890450
• 负责人: Ning Tian
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890450
• 关键词: Animal Model; Behavioral; Blindness; Brain; Cause of Death; Cell Death; Central Nervous System Diseases; Cessation of life; Cytoprotection; Defect; Diabetic Retinopathy; Diagnosis; Disease; Disease model; Electrophysiology (science); Elements; Eye; Eye Injuries; Eye diseases; Family member; Functional disorder; Funding; Genetic; Glaucoma; Glutamate Receptor; Glutamates; Healthcare; Healthcare Systems; Image; Immune; Immune response; In Vitro; Injections; Injury; Lead; Mediating; Mediator of activation protein; Molecular; Mutation; N-Methylaspartate; Nature; Nerve Crush; Neurodegenerative Disorders; Neuronal Injury; Neurons; Neuroprotective Agents; Neurosciences; Optic Nerve; Optic Nerve Injuries; Output; Pathogenesis; Pathologic; Pathologic Processes; Patients; Pharmacology; Play; Predisposition; Prevalence; Process; Property; Proteins; Research; Retina; Retinal Diseases; Retinal Ganglion Cells; Role; Signal Pathway; Signal Transduction; Stem cell transplant; T-Cell Receptor; Therapeutic; Traumatic Brain Injury; Veterans; Vision; Visual; Visual impairment; ZAP-70 Gene; base; cell type; design; disability; effective therapy; excitotoxicity; experimental study; gene therapy; in vivo; inhibitor/antagonist; innovation; insight; neuron loss; neuroprotection; novel; novel therapeutics; preservation; prevent; protective effect; protective efficacy; repaired; retinal ganglion cell degeneration; retinal ischemia; src-Family Kinases; success; treatment strategy

Retinal ganglion cells (RGCs) are the only output neurons that relay visual signals from the eyes to the brain. RGC death is a crucial element in the pathogenesis in many retinal diseases leading to blindness, such as glaucoma and optic nerve injury. These diseases are also the leading causes of blindness of veterans. The prevalence of blinding diseases in veterans is very high and about 20.5-63.4% of veterans were diagnosed with at least one ocular disease. A significant cause of vision defects of VA patients is traumatic optic neuropathy (TON) related to traumatic brain injury (TBI). TBI is a significant cause of death and disability worldwide, and it is estimated 1.6-3.8 million new TBI cases occur in the US each year. About 57-66% veterans with TBI had vision problems and no treatment for TON is more effective than observation. Therefore, the treatment of vision impairment related to TBI is a significant challenge for the VA healthcare system, and it has been limited by incomplete understanding of the molecular mechanisms that mediating the RGC death in these diseases. In addition to the primary injury, secondary injuries dramatically worsen the damage and cause about 40% of TBI deaths. One of the significant secondary injuries of TBI and TON is glutamate excitotoxicity, the pathological process by which neurons are damaged and eventually killed by excessive stimulation of glutamate receptors. This process also plays critical roles in other neurodegenerative diseases, such as glaucoma, which specifically injure RGCs. Therefore, effectively minimizing or preventing glutamate excitotoxicity is crucial to reduce RGCs death and preserve vision. Based on the understanding of the mechanisms which control the vulnerability of RGCs, we plan to develop novel treatment strategies to prevent RGC death in these diseases. Recent studies have shown that immune molecules play essential roles in neuron repair and cell death in CNS diseases. In the retina, the receptors of major histocompatibility complex (MHC) class I molecules, T-cell receptor, (TCR) and their associated proteins are expressed by RGCs. The mutation of these molecules reduced the susceptibility of RGCs to glutamate excitotoxicity and optic nerve crush (ONC). These findings strongly support the possibility that MHCI/TCR could protect RGCs from death. Also, the susceptibility of RGCs to glutamate excitotoxicity and ONC vary significantly among different types of RGC and the types of pathological insults. These results demonstrate that multiple mechanisms regulate the death of RGCs and, therefore, the treatment strategies to prevent RGC death in diseases need to be designed accordingly. In this study, we plan to conduct proof-of-principle studies to establish the role of MHCI-TCR as a critical mediator of neuronal injury induced by glutamate excitotoxicity and ONC. Our preliminary results showed that susceptibility of RGCs to NMDA excitotoxicity and ONC is RGC type-dependent, mutation of CD3z significantly reduces the susceptibility of RGCs, pharmacological inhibition of Src family member, Hck, and ZAP70 protects RGCs, and RGCs express both Hck and ZAP70. We will further determine whether Hck protects RGCs through CD3z activation, whether the protective efficacy of Hck and ZAP70 inhibitors on RGCs is type specific, and whether systemic application of the inhibitors protects RGCs as effective as an intraocular injection (Aim 1). We will also determine whether the protective efficacy of the inhibitors of Hck and ZAP70 on RGCs in ONC is RGC type-dependent (Aim 2). Finally, we will prove the principle of whether the co-application of inhibitors of Hck or ZAP70 with a mGluR1 antagonist protects RGCs synergistically and to establish the optimal strategy for RGC protection (Aim 3). The research will use state-of-art pharmacological, genetic, cellular, imaging, electrophysiological and behavioral approaches, which has several unique advantages: it is grounded in a robust yet entirely novel mechanistic framework built on current neuroscience, it targets multiple ocular injuries and diseases commonly seen in VA patients, and may lead to a novel therapeutic strategy relevant to several eye diseases and TBI in veterans.

视网膜神经节细胞（RGC）是将视觉信号从眼睛传递到大脑的唯一输出神经元。 RGC死亡是许多视网膜疾病的发病机理中的关键因素，例如 青光眼和视神经损伤。这些疾病也是退伍军人失明的主要原因。这 退伍军人中盲目疾病的患病率很高，约有20.5-63.4％的退伍军人被诊断出患有 至少一种眼部疾病。 VA患者视力缺陷的重要原因是创伤性神经病 （TON）与脑外伤有关（TBI）。 TBI是全球死亡和残疾的重要原因，它是 估计每年在美国发生1.6-380万新的TBI案件。大约57-66％的TBI退伍军人 视力问题和无吨治疗比观察更有效。因此，视力的处理 与TBI相关的损害是VA医疗保健系统的重大挑战，它受到了限制 对介导这些疾病中RGC死亡的分子机制的不完全理解。在 除初级伤害外，继发性伤害急剧恶化，损害造成约40％的TBI 死亡人数。 TBI和TON的重大继发损伤之一是谷氨酸兴奋性，病理学 神经元受损并最终被谷氨酸受体刺激过多而杀死的过程。 该过程在其他神经退行性疾病（例如青光眼）中也起着关键作用 伤害RGC。因此，有效地最大程度地减少或预防谷氨酸兴奋性对于减少RGC至关重要 死亡并保持视力。基于对控制脆弱性的机制的理解 RGC，我们计划制定新的治疗策略，以防止这些疾病中的RGC死亡。 最近的研究表明，免疫分子在神经元修复和细胞死亡中起着重要作用 中枢神经系统疾病。在视网膜中，主要组织相容性复合物（MHC）I类分子的受体T细胞 受体，（TCR）及其相关蛋白由RGC表达。这些分子的突变减少了 RGC对谷氨酸兴奋性和视神经挤压（ONC）的敏感性。这些发现强烈 支持MHCI/TCR可以保护RGC免受死亡的可能性。此外，RGC对 不同类型的RGC和病理类型之间的谷氨酸兴奋性和ONC差异很大 侮辱。这些结果表明，多种机制调节了RGC的死亡，因此 需要相应地设计用于防止RGC死亡的治疗策略。 在这项研究中，我们计划进行原则研究，以确立MHCI-TCR作为关键的作用 谷氨酸兴奋性和ONC引起的神经元损伤的介体。我们的初步结果表明 RGC对NMDA兴奋性和ONC的敏感性是RGC类型依赖性的，CD3Z的突变显着 降低RGC的敏感性，SRC家族成员的药理抑制，HCK和ZAP70保护 RGC和RGC同时表达HCK和ZAP70。我们将进一步确定HCK是否通过 CD3z激活，HCK和ZAP70抑制剂对RGCS的保护功效是否是特定于类型的，并且 抑制剂的全身应用是否保护像眼内注射一样有效的RGC（AIM 1）。我们 还将确定HCK和ZAP70在ONC中的RGC抑制剂的保护性疗效是否为RGC 依赖类型（AIM 2）。最后，我们将证明是HCK抑制剂的共同应用还是 具有MGLUR1拮抗剂的ZAP70协同保护RGC并建立RGC的最佳策略 保护（目标3）。该研究将使用最先进的药理，遗传，细胞，成像， 电生理和行为方法，具有多种独特的优势：它以强大的 然而，完全新颖的机械框架建立在当前的神经科学上，它针对多个眼部损伤和 在VA患者中常见的疾病，可能导致与几只眼睛有关的新型治疗策略 退伍军人的疾病和TBI。