Programmed cell death and cytomegalovirus retinitis pathogenesis

项目主任/首席调查员(最后、第一、中间)：DIX，Richard D 项目摘要 程序性细胞死亡(PCD)在先天免疫过程中起作用，清除受病毒感染的细胞并调节 病毒入侵期间的感染相关炎症。几乎没有关于准确的 PCD在病毒性视网膜疾病发病机制中的作用，尤其是由 疱疹病毒包括艾滋病相关的人类巨细胞病毒(HCMV)视网膜炎。取得进展的关键障碍 在提高我们诊断、预防和/或治疗疱疹病毒视网膜疾病的能力方面，一直缺乏 关于不同形式的PCD在这些疾病的发生和发展中的可能贡献的信息 病毒引起的视网膜疾病，包括艾滋病相关的巨细胞病毒视网膜炎。我们的目标是解决这一知识 赤字和通过获得确定相对个人所需的新信息而取得进展的关键障碍 以及细胞凋亡、坏死性下垂和下垂在这种视觉的发生和发展过程中的集体作用- 利用已建立的小鼠巨细胞病毒(MCMV)视网膜炎模型威胁眼病 逆转录病毒诱导的免疫抑制小鼠(MAIDS)。我们的中心假设是细胞凋亡， 坏死性下垂和上睑下垂通过不同的机制共同作用于严重的视网膜组织。 佣人相关MCMV视网膜炎发病过程中的破坏。我们的目标是使用女佣模式 MCMV视网膜炎的诊断：(1)获得所需的信息，以了解确切的贡献，并开始 了解这些PCD通路促进视网膜组织破坏和丢失的机制 功能，(2)探索这些PCD通路刺激视网膜内炎症的机制 组织在视网膜疾病的发生和发展中的作用，以及(3)证实PCD抑制剂代表着一种新的 巨细胞病毒视网膜病变的治疗方法。这些目标将通过以下途径实现 成功完成三个具体目标：(1)检验多个PCD途径有助于 在佣人相关的MCMV视网膜炎发病机制中视网膜组织破坏，(2)检验PCD- 引发的炎症在女佣相关视网膜组织破坏的发展中起着关键作用 MCMV视网膜炎的发病机制，以及(3)检验PCD抑制剂将改变发病和 女佣相关的MCMV视网膜炎的进展。 PHS 398/2590(06/09版)页面续格式页面

Program Director/Principal Investigator (Last, First, Middle): Dix, Richard D Project Summary Programmed cell death (PCD) operates during innate immunity to eliminate virus-infected cells and regulate infection-associated inflammation during virus invasion. Little information is available regarding the precise contributions of PCD toward the pathogenesis of retinal diseases of virus origin, especially those caused by herpesviruses including AIDS-related human cytomegalovirus (HCMV) retinitis. A critical barrier to progress in advancing our ability to diagnose, prevent, and/or treat herpesvirus retinal diseases has been a lack of information on the possible contributions of different forms of PCD toward onset and development of these virus-induced retinal diseases including AIDS-related HCMV retinitis. Our goal is to address this knowledge deficit and the critical barrier to progress by obtaining new information needed to define the relative individual and collective roles of apoptosis, necroptosis, and pyroptosis during onset and development of this sight- threatening eye disease using an established mouse model of murine cytomegalovirus (MCMV) retinitis in mice with retrovirus-induced immunosuppression (MAIDS). Our central hypothesis is that apoptosis, necroptosis, and pyroptosis conspire via different mechanisms to contribute to the severe retinal tissue destruction during MAIDS-related MCMV retinitis pathogenesis. Our objectives are to use the MAIDS model of MCMV retinitis to (1) obtain the information needed to understand the precise contributions and begin to understand the mechanisms by which these PCD pathways contribute to retinal tissue destruction and loss of function, (2) explore the mechanisms by which these PCD pathways stimulate inflammation within retinal tissues during retinal disease onset and development, and (3) establish that PCD inhibitors represent a new therapeutic approach for management of cytomegalovirus retinal disease. These objectives will be met through successful completion of three Specific Aims: (1) test the hypothesis that multiple PCD pathways contribute to retinal tissue destruction during MAIDS-related MCMV retinitis pathogenesis, (2) test the hypothesis that PCD- initiated inflammation plays a critical role in development of retinal tissue destruction during MAIDS-related MCMV retinitis pathogenesis, and (3) test the hypothesis that PCD inhibitors will alter the onset and progression of MAIDS-related MCMV retinitis. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page