Immune responses in traumatic RGC death

创伤性 RGC 死亡中的免疫反应

• 批准号: 8924256
• 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 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8924256
• 关键词: Antibodies; Area; Axon; Blindness; Blood Vessels; Brain; Brain Diseases; CD3 Antigens; Caring; Cause of Death; Cell Death; Cells; Central Nervous System Diseases; Cessation of life; Data; Defect; Dendrites; Development; Diabetes Mellitus; Disease; Eye; Eye diseases; Foundations; Gene Mutation; Genes; Glaucoma; Glutamate Receptor; Glutamates; Goals; Healthcare; Healthcare Systems; Immune; Immune response; In Vitro; Injury; Locomotor Recovery; Major Histocompatibility Complex; Mediating; Modeling; Molecular; Monoclonal Antibody HuM291; Motor Neurons; Mus; Mutation; N-Methylaspartate; Nerve Crush; Nervous system structure; Neurodegenerative Disorders; Neurons; Optic Nerve; Optic Nerve Injuries; Pathologic Processes; Pathway interactions; Patients; Play; Population; Prevention; Process; Proteins; Regulation; Resistance; Retina; Retinal Ganglion Cells; Role; Signal Transduction; Spinal cord injury; Stroke; Structure; T-Cell Receptor; Testing; Therapeutic; Time; Transgenic Mice; Trauma; Traumatic Brain Injury; Traumatic injury; Veterans; Vision; Visual; Work; alternative treatment; disability; effective therapy; excitotoxicity; experience; gene therapy; improved; in vivo; injured; insight; killings; neuron development; neuron loss; non-genetic; overexpression; prevent; public health relevance; receptor; repaired; research study; treatment strategy

 DESCRIPTION (provided by applicant): Traumatic injuries of the nervous system, such as traumatic brain injury (TBI), spinal cord injury (SCI) and traumatic optic neuropathy (TON), are major causes of death and disability in the USA and major challenges for the healthcare of veterans. In addition to the primary injury, secondary injuries, which occur after the primary injury dramatically worsens the damage and cause about 40% of TBI deaths. Because little can be done to reverse the primary injury, the primary aim of the treatment is to prevent secondary injury induced neuronal death. One of the major secondary injuries of TBI, SCI and TON is glutamate excitotoxicity, the pathological process by which neurons are damaged and eventually killed by excessive stimulation of glutamate receptors. Therefore, effectively minimizing or preventing glutamate excitotoxicity will reduce the secondary injury to neurons. In addition, glutamate excitotoxicity also plays critical roles in many other neurodegenerative diseases, such as glaucoma, the leading cause of blindness in the world, including veteran population. Both TON and glaucoma specifically injure retinal ganglion cells (RGCs). Because RGCs are the only cells relaying the visual signals from the eyes to the brain, loss of RGCs will result in an irreversible loss of vision and no effective treatments are currently available. Therefore, preventing RGCs from death in TON and glaucoma is crucial to preserve vision. Understanding the mechanisms which control the vulnerability of RGCs to glutamate excitotoxicity, TON or glaucoma will help us to develop treatment strategies to prevent RGC death in these diseases. Recent studies have shown that immune molecules play important 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. Mutation of these molecules compromised RGC dendrite and axon structure and increased the vulnerability of RGCs to glutamate excitotoxicity while up-regulated MHCI expression in motor neurons significantly promoted the recovery of locomotor abilities after SCI. These findings strongly support the possibility that MHCI/TCR could protect RGCs from death. In this study, we plan to characterize the vulnerability of RGCs to glutamate excitotoxicity and optic nerve crush (ONC), investigate the roles of TCR in the regulation of RGC vulnerability, and determine the therapeutic potential of activation of TCR for the prevention of RGC death. The first goal of this study is to determine the contribution of a key molecule of TCR, CD3, to the vulnerability of RGCs. Our preliminary results showed that different subtypes of RGCs have different vulnerability to glutamate excitotoxicity and RGC vulnerability to glutamate excitotoxicity is dramatically increased in CD3-/- mice. We will further characterize the vulnerability of four subtypes of RGCs to glutamate excitotoxicity and ONC, and the contribution of CD3to RGC vulnerability. The second goal is to determine the therapeutic potential of overexpressing CD3 to protect RGCs. Our preliminary results demonstrated that expressing CD3 in RGCs of CD3-/- retinas restored the RGC dendritic defects, suggesting the reversibility of CD3-mediated effects on RGCs. We plan to further determine whether the resistance of RGCs can be enhanced by over-expressing the gene encoding CD3. The third goal of this study is to determine the therapeutic potentials of CD3 activating molecules to protect RGCs. It has been demonstrated that CD3 could be activated by exogenous CD3 activating molecules in vitro. We will further determine if the exogenous CD3activating molecules work synergistically with the over-expression of CD3 to protect RGCs. Overall, this study will identify the role of MHCI-TCR in the regulation of the vulnerability of RGCs to pathological insults, and test the potential of using MHCI/TCR mediated mechanisms to protect RGCs from death in diseases. Although RGCs are used as a model in this study, the results could provide important insights into the neuronal death of other areas of CNS and, therefore, have important implications in neuronal protection following traumatic injuries in the CNS.

 描述（由申请人提供）： 神经系统的创伤性损伤，例如创伤性脑损伤（TBI）、脊髓损伤（SCI）和创伤性视神经病变（TON），是美国死亡和残疾的主要原因，也是退伍军人医疗保健的主要挑战。除了原发性损伤外，继发性损伤（发生在原发性损伤之后）大大加重了损伤，并导致约40%的TBI死亡。由于几乎无法逆转原发性损伤，因此治疗的主要目的是防止继发性损伤诱导的神经元死亡。TBI、SCI和TON的主要继发性损伤之一是谷氨酸兴奋性毒性，即神经元因谷氨酸受体的过度刺激而受损并最终死亡的病理过程。因此，有效地减少或防止谷氨酸兴奋毒性将减少对神经元的二次损伤。此外，谷氨酸兴奋性毒性在许多其他神经退行性疾病中也起着关键作用，例如青光眼，青光眼是世界上包括退伍军人在内的主要致盲原因。TON和青光眼都特异性损伤视网膜神经节细胞（RGC）。由于RGC是将视觉信号从眼睛传递到大脑的唯一细胞，因此RGC的丧失将导致不可逆的视力丧失，目前尚无有效的治疗方法。因此，防止视网膜节细胞在TON和青光眼中死亡对于保护视力至关重要。了解控制RGC对谷氨酸兴奋毒性、TON或青光眼的脆弱性的机制将有助于我们开发治疗策略以预防这些疾病中的RGC死亡。最近的研究表明，免疫分子在中枢神经系统疾病的神经元修复和细胞死亡中起重要作用。在视网膜中，主要组织相容性复合体（MHC）I类分子的受体、T细胞受体（TCR）及其相关蛋白由RGCs表达。这些分子的突变损害了RGC树突和轴突结构，并增加了RGC对谷氨酸兴奋性毒性的脆弱性，而运动神经元中MHCI表达的上调显著促进了SCI后运动能力的恢复。这些发现强烈支持MHCI/TCR可以保护RGC免于死亡的可能性。在这项研究中，我们计划表征RGC对谷氨酸兴奋性毒性和视神经挤压（ONC）的脆弱性，研究TCR在RGC脆弱性调节中的作用，并确定TCR活化预防RGC死亡的治疗潜力。本研究的第一个目标是确定TCR的关键分子CD 3 β对RGC脆弱性的贡献。我们的初步结果表明，不同亚型的RGCs对谷氨酸兴奋毒性的脆弱性不同，并且在CD 3 +/-小鼠中，RGCs对谷氨酸兴奋毒性的脆弱性显著增加。我们将进一步描述四种RGC亚型对谷氨酸兴奋毒性和ONC的脆弱性，以及CD 3受体对RGC脆弱性的贡献。第二个目标是确定过表达CD 3 β保护RGC的治疗潜力。我们的初步结果表明，在CD 3 β-/-视网膜的RGC中表达CD 3 β可以恢复RGC树突状缺陷，这表明CD 3 β介导的对RGC的作用是可逆的。我们计划进一步确定是否可以通过过表达编码CD 3 β的基因来增强RGCs的抗性。本研究的第三个目标是确定CD 3 β活化分子保护RGCs的治疗潜力。体外研究表明，外源性CD 3 β激活分子可激活CD 3 β。我们将进一步确定外源性CD 3 β活化分子是否与CD 3 β过表达协同作用以保护RGCs。总之，本研究将确定MHCI-TCR在调节RGCs对病理损伤的脆弱性中的作用，并测试使用MHCI-TCR的潜力。 MHCI/TCR介导的保护RGCs免于疾病死亡的机制。虽然RGC在这项研究中被用作模型，结果可以提供重要的见解CNS的其他领域的神经元死亡，因此，在CNS创伤性损伤后的神经元保护具有重要意义。