How Do Astrocytes Participate in Demyelination and Myelin Repair

星形胶质细胞如何参与脱髓鞘和髓磷脂修复

• 批准号: 10739783
• 负责人: Crystal K Colón Ortiz
• 金额: $ 7.26万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739783
• 关键词: How; Do; Astrocytes; Participate; Demyelination

PROJECT SUMMARY Stroke and traumatic brain injury (TBI) cause alterations to the vasculature, disrupting the neurovascular unit (NVU) and causing neuroinflammation and neuronal death. In response to vascular damage, glial cells of the central nervous system (CNS), astrocytes and microglia, produce pro-inflammatory cytokines that can contribute to neuronal death. However, the specific signaling that connects the damaged neurovasculature to the glial response after injury remains to be understood. The eye, as CNS tissue, allow us to study the interactions between the vasculature and glial cells. Similar to human pathology, Retinal Vein Occlusion (RVO) in mice causes retinal edema, inflammation, and neuronal death; providing a model to study these interactions. Using this model, previous studies in our lab identified non-apoptotic activation of the protease caspase-9, that is usually associated with cell death, in the endothelium. Inhibiting caspase-9 or genetically deleting it from the endothelium, protects the retina from edema and neuronal death. These results indicated that expression of endothelial caspase-9 (EC Casp9) leads to neurodegeneration after vascular injury. Furthermore, we discovered that inhibiting caspase-9 significantly reduces the activity of caspase-6 (executioner caspase that can be activated by caspase-9) in astrocytes, but not microglia. Activation of caspase-6 in astrocytes is associated with increased cleavage and hyper-aggregation of GFAP and production of pro-inflammatory cytokines. I hypothesize that non-apoptotic activation of EC Casp9 increases astroglial caspase-6 which will result in the cleavage of GFAP, production of inflammatory cytokines, and neurodegeneration P-RVO. The long-term objective of this proposal is to study the role of caspase-9 signaling in vascular-glial communication and its contribution to increased pro-inflammatory cytokine and neurodegeneration. Studies in EC Casp9 KO mice revealed that EC Casp9 activates astroglial caspase-6. To further test the role of caspase-9 signaling on vascular-astroglial communication, we will determine if astroglial caspase-9 (1) is upstream of astroglial caspase-6 and mediates GFAP cleavage in RVO, (2) increases the production of pro-inflammatory cytokines, and (3) leads to retinal neuronal death and visual pathway dysfunction. Understanding vascular-glial signaling in neurovascular injury can help in the discovery of novel therapeutic targets for neuroprotection. The focus of the postdoctoral phase will be to study caspase signaling in glial cells and its contribution to retinal ganglion loss in Optic Neuritis associated with Multiple Sclerosis (MS). The ultimate goal of this F99/K00 proposal is to prepare me to be a principal investigator and study how neuroinflammation is regulated in neurodegenerative diseases of the brain that also affect the eye. To accomplish these goals, I developed a plan with mentors and collaborators to guide my specific research and professional activities. With the opportunities for scientific and career development available at Columbia, the objectives of this proposal are expected to be achieved.

项目摘要 中风和创伤性脑损伤（TBI）导致血管系统改变，破坏神经血管单元 (NVU)并导致神经炎症和神经元死亡。为了应对血管损伤，脑胶质细胞 中枢神经系统（CNS），星形胶质细胞和小胶质细胞，产生促炎细胞因子， 神经元死亡然而，连接受损神经血管和神经胶质细胞的特定信号 受伤后的反应仍有待了解。眼睛作为中枢神经系统组织，使我们能够研究 血管和神经胶质细胞之间的联系与人类病理学相似，小鼠视网膜静脉阻塞（RVO） 导致视网膜水肿、炎症和神经元死亡;提供了研究这些相互作用的模型。使用 在这个模型中，我们实验室以前的研究确定了蛋白酶caspase-9的非凋亡激活，即 通常与内皮细胞死亡有关。抑制半胱天冬酶-9或从基因上将其删除， 内皮细胞，保护视网膜免于水肿和神经元死亡。这些结果表明， 内皮半胱天冬酶-9（EC Casp 9）导致血管损伤后的神经变性。此外，我们发现， 抑制半胱天冬酶-9显著降低了半胱天冬酶-6的活性（可以被 由半胱天冬酶-9激活）在星形胶质细胞中，而不是在小胶质细胞中。星形胶质细胞中caspase-6的激活与 增加GFAP的裂解和过度聚集以及促炎细胞因子的产生。我假设 EC Casp 9的非凋亡激活增加了星形胶质细胞caspase-6，这将导致 GFAP、炎性细胞因子的产生和神经变性P-RVO。长期目标是 这项研究的目的是研究caspase-9信号在血管-神经胶质细胞通讯中的作用， 增加促炎细胞因子和神经变性。在EC Casp 9 KO小鼠中的研究显示，EC Casp 9激活星形胶质细胞caspase-6。为了进一步检测caspase-9信号在血管-星形胶质细胞中的作用， 为了进一步研究星形胶质细胞caspase-9（1）是否位于星形胶质细胞caspase-6的上游，并介导 RVO中GFAP裂解，（2）增加促炎细胞因子的产生，（3）导致视网膜病变。 神经元死亡和视觉通路功能障碍。了解神经血管损伤中的血管-胶质细胞信号传导 可以帮助发现新的神经保护治疗靶点。博士后阶段的重点 将研究神经胶质细胞中的半胱天冬酶信号及其在视神经炎视网膜神经节丢失中的作用 多发性硬化症（MS）。这个F99/K 00提案的最终目标是让我做好准备， 首席研究员，研究神经炎症如何在大脑神经退行性疾病中调节 也会影响眼睛为了实现这些目标，我与导师和合作者制定了一个计划， 我的具体研究和专业活动。科学和职业发展的机会 在哥伦比亚可用，这个建议的目标有望实现。