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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

项目主管/首席研究员（最后、第一、中）：Dix, Richard D