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

基本信息

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
项目类别：
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

项目摘要

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

项目总监/首席研究员（最后、第一、中间）：Dix, Richard D 项目概要程序性细胞死亡（PCD）在先天免疫过程中发挥作用，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。关于精确度的信息很少 PCD 对病毒源性视网膜疾病（尤其是由病毒引起的视网膜疾病）发病机制的贡献疱疹病毒，包括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/或治疗疱疹病毒性视网膜疾病的能力方面一直缺乏有关不同形式的 PCD 对这些疾病的发生和发展可能做出的贡献的信息病毒引起的视网膜疾病，包括艾滋病相关的 HCMV 视网膜炎。我们的目标是解决这些知识缺陷和通过获取定义相关个体所需的新信息来取得进展的关键障碍以及细胞凋亡、坏死性凋亡和焦亡在这种景象的发生和发展过程中的集体作用—— 使用已建立的鼠巨细胞病毒（MCMV）视网膜炎小鼠模型来研究威胁性眼部疾病患有逆转录病毒诱导的免疫抑制（MAIDS）的小鼠。我们的中心假设是细胞凋亡，坏死性凋亡和焦亡通过不同的机制共同导致严重的视网膜组织 MAIDS 相关 MCMV 视网膜炎发病机制中的破坏。我们的目标是使用 MAIDS 模型 MCMV 视网膜炎 (1) 获取了解精确贡献所需的信息并开始了解这些 PCD 途径导致视网膜组织破坏和丧失的机制功能，（2）探索这些PCD途径刺激视网膜内炎症的机制 (3) 确定 PCD 抑制剂代表了一种新的视网膜疾病发生和发展过程中的组织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) 检验多种 PCD 途径有助于的假设 MAIDS 相关 MCMV 视网膜炎发病机制期间视网膜组织的破坏，(2) 检验 PCD- 的假设引发的炎症在 MAIDS 相关的视网膜组织破坏的发展中起着关键作用 MCMV 视网膜炎发病机制，以及 (3) 检验 PCD 抑制剂将改变发病机制的假设 MAIDS 相关 MCMV 视网膜炎的进展。 PHS 398/2590（修订版 06/09）页面延续格式页面