Programmed cell death and cytomegalovirus retinitis pathogenesis

程序性细胞死亡和巨细胞病毒性视网膜炎发病机制

• 批准号: 10655133
• 负责人: Richard D Dix
• 金额: $ 40.17万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655133
• 关键词: Acquired Immunodeficiency Syndrome; Address; Apoptosis; Blindness; Cell Death; Cells; Cytomegalovirus; Cytomegalovirus Retinitis; Development; Diagnosis; Eye; Eye diseases; Frequencies; Goals; HIV; Herpesviridae; Human; Immunologics; Immunosuppression; In Vitro; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Infiltrate; Invaded; Knowledge; Lead; Mediating; Messenger RNA; Mission; Murid herpesvirus 1; Mus; Natural Immunity; Onset of illness; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Performance; Persons; Play; Predisposition; Principal Investigator; Protein Kinase Interaction; Proteins; Public Health; RIPK1 gene; Research; Retina; Retinal Diseases; Retinitis; Retroviridae; Role; Severities; Testing; Time; Tissues; Virus; Virus Diseases; Vision; Z-DNA Binding Protein; cell type; inhibitor; loss of function; mouse model; mutant; novel therapeutic intervention; prevent; programs; recruit; virus development

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

计划主任/首席研究员（最后，第一，中间）：DIX，理查德·D 项目摘要 在先天免疫力期间，程序性细胞死亡（PCD）可消除病毒感染的细胞并调节 病毒入侵期间与感染相关的炎症。关于精确的信息很少 PCD对病毒起源视网膜疾病的发病机理的贡献，尤其是由 疱疹病毒在内，包括与艾滋病相关的人类巨细胞病毒（HCMV）视网膜炎。进步的关键障碍 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缺乏 有关不同形式的PCD对发作和开发的可能贡献的信息 病毒引起的视网膜疾病，包括与艾滋病相关的HCMV视网膜炎。我们的目标是解决这一知识 赤字和进步的关键障碍通过获得定义相对个体所需的新信息 在发作和发展过程中凋亡，坏死和凋亡的集体作用 - 使用已建立的小鼠巨细胞病毒（MCMV）视网膜炎威胁眼病 具有逆转录病毒诱导的免疫抑制（女仆）的小鼠。我们的中心假设是凋亡， 坏死性和凋亡通过不同的机制促进严重的视网膜组织 与女仆相关的MCMV视网膜炎发病机理中的破坏。我们的目标是使用女佣模型 MCMV视网膜炎的（1）获得了解确切贡献所需的信息并开始 了解这些PCD途径有助于视网膜组织破坏和丧失的机制 功能，（2）探索这些PCD途径在视网膜内刺激炎症的机制 视网膜疾病发作和发育过程中的组织，（3）确定PCD抑制剂代表了一种新的 用于管理巨细胞病毒视网膜疾病的治疗方法。这些目标将通过 成功完成三个具体目标：（1）测试多个PCD途径有助于的假设 在女仆相关的MCMV视网膜炎发病机理期间，视网膜组织破坏，（2）检验了PCD-的假设 引发的炎症在与女仆有关的视网膜组织破坏的发展中起着至关重要的作用 MCMV视网膜炎发病机理，（3）检验了PCD抑制剂将改变发作和 与女仆相关的MCMV视网膜炎的进展。 PHS 398/2590（修订版06/09）页面延续格式页面