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Immune Responses in Neuronal Cell Death

神经细胞死亡中的免疫反应

基本信息

批准号：
10554292
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
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-10-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10554292
关键词：
Animal Model Behavioral Blindness Brain Brain Injuries 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 Mediating Mediator 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 Play Predisposition Prevalence Probability Process Property Proteins Research Retina Retinal Diseases Retinal Ganglion Cells Role Signal Pathway Signal Transduction Src family kinase inhibitor PP2 Stem cell transplant T-Cell Receptor Therapeutic Traumatic Brain Injury Veterans Vision Visual Visual impairment ZAP-70 Gene antagonist cell type design disability effective therapy efficacy validation excitotoxicity experimental study gene therapy in vivo inhibitor innovation insight neuron loss neuroprotection novel novel therapeutic intervention pharmacologic preservation prevent protective effect protective efficacy repaired retinal ganglion cell degeneration retinal ischemia success treatment strategy visual dysfunction

项目摘要

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）是唯一将视觉信号从眼睛传递到大脑的输出神经元。 RGC 死亡是许多导致失明的视网膜疾病发病机制的关键因素，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。这退伍军人中致盲性疾病的患病率非常高，大约 20.5-63.4% 的退伍军人被诊断出患有这种疾病至少一种眼部疾病。 VA患者视力缺陷的一个重要原因是外伤性视神经病变（TON）与创伤性脑损伤（TBI）有关。 TBI 是全世界死亡和残疾的一个重要原因，据估计，美国每年有 1.6-380 万新发 TBI 病例。大约 57-66% 患有 TBI 的退伍军人曾对于视力问题，没有任何治疗方法比观察更有效。因此，治疗视力与 TBI 相关的损害对 VA 医疗保健系统来说是一个重大挑战，并且受到以下因素的限制：对介导这些疾病中 RGC 死亡的分子机制的了解不完全。在除了原发性损伤外，继发性损伤会使损伤急剧恶化，约 40% 的 TBI 是由继发性损伤引起的死亡人数。 TBI 和 TON 的重要继发性损伤之一是谷氨酸兴奋性毒性，即病理性损伤神经元因谷氨酸受体的过度刺激而受损并最终被杀死的过程。这一过程在其他神经退行性疾病中也发挥着关键作用，例如青光眼，特别是损伤 RGC。因此，有效减少或预防谷氨酸兴奋毒性对于减少 RGC 至关重要死亡并保留视力。基于对控制脆弱性的机制的理解 RGC，我们计划开发新的治疗策略来预防这些疾病中的 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发挥着重要作用。中枢神经系统疾病。在视网膜中，主要组织相容性复合体 (MHC) I 类分子、T 细胞的受体受体 (TCR) 及其相关蛋白由 RGC 表达。这些分子的突变减少了 RGC 对谷氨酸兴奋性毒性和视神经挤压 (ONC) 的敏感性。这些发现强烈支持 MHCI/TCR 可以保护 RGC 免于死亡的可能性。此外，RGC 的敏感性谷氨酸兴奋毒性和 ONC 在不同类型的 RGC 和病理类型之间存在显着差异侮辱。这些结果表明，多种机制调节 RGC 的死亡，因此，需要相应地设计预防 RGC 因疾病而死亡的治疗策略。在本研究中，我们计划进行原理验证研究，以确定 MHCI-TCR 作为关键的作用谷氨酸兴奋性毒性和 ONC 诱导的神经元损伤的介质。我们的初步结果表明 RGCs 对 NMDA 兴奋性毒性的易感性和 ONC 是 RGC 类型依赖性的，CD3z 突变显着降低 RGC 的易感性，Src 家族成员、Hck 和 ZAP70 的药理抑制可保护 RGCs 和 RGCs 均表达 Hck 和 ZAP70。我们将进一步确定 Hck 是否通过以下方式保护 RGC： CD3z 激活，Hck 和 ZAP70 抑制剂对 RGC 的保护功效是否具有类型特异性，以及全身应用抑制剂是否能像眼内注射一样有效地保护 RGC（目标 1）。我们还将确定 Hck 和 ZAP70 抑制剂对 ONC 中 RGC 的保护功效是否为 RGC 类型相关（目标 2）。最后，我们将证明Hck或Hck抑制剂联合应用的原理。 ZAP70 与 mGluR1 拮抗剂协同保护 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学、遗传、细胞、成像、电生理学和行为学方法，具有几个独特的优势：然而，它是建立在当前神经科学基础上的全新机制框架，它针对多种眼部损伤和 VA 患者常见的疾病，可能会导致与多种眼部相关的新治疗策略退伍军人的疾病和 TBI。