Irving Estevez_Diversity Supplement: R01 NS120895

摘要 星形胶质细胞是一种多功能的神经胶质细胞，调节中枢神经系统(CNS)的不同过程。 星形胶质细胞在疾病中的作用是复杂的，包括保护和病理功能。最近， 不同的星形胶质细胞激活状态已被描述，尽管支配星形胶质细胞的分子机制 嗜神经性病毒感染过程中的极化还不是很清楚。在这里，我们提出受体相互作用 蛋白激酶-3(RIPK3)是病毒感染过程中炎性星形胶质细胞激活的未知驱动因子 中枢神经系统感染。虽然RIPK3在细胞程序性死亡中的作用已经被广泛描述，但我们的 已发表的工作已经描述了该通路在协调中的多效性、细胞死亡无关的功能 病毒性脑炎期间的保护性神经炎症。在初步研究中，我们现在表明RIPK3 在寨卡病毒攻击后，星形胶质细胞中的信号是生存和病毒学控制所必需的 全球关注的新出现的嗜神经性病原体。使用新的老鼠遗传工具的组合，我们将 通过1)定义表达、激活和抗病毒的谱来阐明RIPK3信号在星形胶质细胞中的作用 星形细胞RIPK3的功能；2)确定星形细胞RIPK3信号在协调中的作用 神经炎症；以及3)确定星形胶质细胞中RIPK3信号的关键底物和转录输出。 总之，我们的研究有望确定保护神经免疫功能的新分子机制。 在病毒性脑炎期间。

Abstract Astrocytes are versatile glial cells that regulate diverse processes in the central nervous system (CNS). Roles for astrocytes during disease are complex and include both protective and pathologic functions. Recently, distinct astrocyte activation states have been described, though the molecular mechanisms that govern astrocyte polarization during neurotropic viral infection are not well understood. Here, we propose that receptor-interacting protein kinase-3 (RIPK3) is a previously unappreciated driver of inflammatory astrocyte activation during viral infection of the CNS. While roles for RIPK3 in programmed cell death have been extensively characterized, our published work has described pleiotropic, cell death-independent functions for this pathway in the coordination of protective neuroinflammation during viral encephalitis. In preliminary studies, we now show that RIPK3 signaling in astrocytes is required for survival and virologic control following challenge with Zika virus, an emerging neurotropic pathogen of global concern. Using a combination of novel mouse genetic tools, we will elucidate roles for RIPK3 signaling in astrocytes by 1) Defining profiles of expression, activation, and antiviral function for astrocytic RIPK3; 2) Determining roles for astrocytic RIPK3 signaling in coordinating neuroinflammation; and 3) Defining key substrates and transcriptional outputs of RIPK3 signaling in astrocytes. Together, our studies promise to identify new molecular mechanisms governing protective neuroimmune function during viral encephalitis.