Pathogenesis of CMV Retinitis

巨细胞病毒视网膜炎的发病机制

• 批准号: 7490436
• 负责人: Richard D Dix
• 金额: $ 33.84万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7490436
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adoptive Transfer; Antiviral Agents; Apoptosis; Attention; Biological Assay; C57BL/6 Mouse; Cell Count; Cell Death; Cells; Cessation of life; Clinical; Complication; Cytomegalovirus; Cytomegalovirus Retinitis; Cytopathology; Cytotoxic T-Lymphocytes; Data; Disease; Effector Cell; Event; Evolution; Exhibits; Funding; Genetic; Goals; Highly Active Antiretroviral Therapy; Human; Immunocompetent; Immunologic Deficiency Syndromes; Immunologics; Immunosuppression; Immunotherapy; Incidence; Infection; Interleukin-2; Interleukin-4; Knock-out; Laboratories; Lymphocyte; Measurement; Mediating; Messenger RNA; Mononuclear; Muller' s cell; Murine Acquired Immunodeficiency Syndrome; Mus; Natural Killer Cells; Numbers; Pathogenesis; Pathway interactions; Patients; Peripheral; Persons; Play; Population; Predisposition; Production; Protein Overexpression; Relative (related person); Research Personnel; Resistance; Retinal; Retinal Diseases; Retinitis; Retroviridae; Reverse Transcriptase Polymerase Chain Reaction; Role; Series; Severities; Source; T-Lymphocyte; TNFRSF1A gene; Testing; Therapeutic; Therapeutic immunosuppression; Thinking; Time; Tissues; Today; Transcriptional Activation; Transgenic Mice; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Up-Regulation; Virus; Vision; Work; cell killing; clinically relevant; cytotoxic; cytotoxicity; design; human TNF protein; innovation; insight; macrophage; mouse model; mouse perforin; novel; novel diagnostics; perforin; research study; retinal neuron

DESCRIPTION: Human cytomegalovirus (HCMV) retinitis remains a significant ophthalmologic problem in patients with HIV/AIDS. Three specific aims are proposed to continue study of the basic pathophysiologic pathways and mechanisms that mediate retinal infection and retinal destruction during evolution of AIDS-related HCMV retinal. These aims will use a clinically relevant mouse model of murine CMV (MCMV) retinitis novel to our laboratory in which MCMV is inoculated subretinally into C57BL/6 mice with MAIDS, a murine retrovirus-induced immunodeficiency syndrome. The first aim will determine if quantification of loss of the perforin cytotoxic pathway is a better predictor for susceptibility to MCMV retinitis than quantification of absolute numbers of peripheral lymphocytes during MAIDS progression. Subsequent experiments of this aim will focus on measurement of the perforin cytotoxic pathway in HIV/AIDS patients with or without HCMV retinitis using an innovative RT-PCR assay for human perforin mRNA. The second aim will determine the pathway by which perforin-mediated cytotoxicity is suppressed during MAIDS to allow susceptibility to MCMV retinitis. These experiments will focus on interleukin-4 which is upregulated during MAIDS and thought to shift cytotoxic T-cell killing from a dominant perforin pathway to a dominant Fas/FasL pathway. The third aim will determine the contribution of tumor necrosis factor-a (TNF-a)-induced apoptosis in mediating retinal tissue destruction during MAIDS-related MCMV retinitis with special attention to retinal neurons not infected with virus. The proposed studies will provide new insights into the virologic, immunologic, and pathogenetic events that operate during evolution of retinal disease in the unique setting of retrovirus-induced immuno-suppression, information needed to develop new diagnostic strategies to better predict onset of HCMV retinitis in HIV/AIDS patients and to develop rational therapeutic strategies to better manage this sight-threatening disease in the clinical setting.

描述：人类巨细胞病毒 (HCMV) 视网膜炎仍然是 HIV/AIDS 患者的一个重要眼科问题。提出了三个具体目标，以继续研究艾滋病相关 HCMV 视网膜进化过程中介导视网膜感染和视网膜破坏的基本病理生理途径和机制。这些目标将使用我们实验室新颖的临床相关的小鼠巨细胞病毒（MCMV）视网膜炎小鼠模型，其中将 MCMV 视网膜下接种到患有 MAIDS（一种小鼠​​逆转录病毒诱导的免疫缺陷综合征）的 C57BL/6 小鼠中。第一个目标将确定，与 MAIDS 进展期间外周淋巴细胞绝对数量的量化相比，穿孔素细胞毒性途径损失的量化是否能更好地预测 MCMV 视网膜炎的易感性。该目标的后续实验将侧重于使用创新的人穿孔素 mRNA RT-PCR 测定法来测量患有或不患有 HCMV 视网膜炎的 HIV/AIDS 患者的穿孔素细胞毒性途径。第二个目标是确定 MAIDS 期间穿孔素介导的细胞毒性被抑制的途径，从而导致对 MCMV 视网膜炎的易感性。这些实验将重点关注白介素 4，它在 MAIDS 期间上调，并被认为可以将细胞毒性 T 细胞杀伤从占主导地位的穿孔素途径转变为占主导地位的 Fas/FasL 途径。 第三个目标将确定肿瘤坏死因子-a (TNF-a) 诱导的细胞凋亡在 MAIDS 相关 MCMV 视网膜炎期间介导视网膜组织破坏中的作用，特别关注未感染病毒的视网膜神经元。拟议的研究将为在逆转录病毒诱导的免疫抑制的独特环境下视网膜疾病演变过程中的病毒学、免疫学和致病事件提供新的见解，为开发新的诊断策略以更好地预测 HIV/AIDS 患者中 HCMV 视网膜炎的发病以及制定合理的治疗策略以在临床环境中更好地管理这种威胁视力的疾病所需的信息提供信息。