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）视网膜炎仍然是艾滋病毒/艾滋病患者的重大眼科问题。提出了三个具体的目的，以继续研究与AIDS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。这些目的将对我们的实验室使用临床相关的小鼠CMV（MCMV）视网膜炎小鼠模型，其中MCMV用鼠辅助接收到与女仆的C57BL/6小鼠，这是鼠逆转录病毒诱导的免疫缺陷综合征。第一个目的将确定量化性细胞毒性途径丢失的定量是否比对女仆进展过程中的绝对数量的外周淋巴细胞数量的量化更好地预测了对MCMV视网膜炎的易感性。此目标的随后实验将重点介绍用于使用人类穿孔蛋白mRNA的创新的RT-PCR测定法中，患有或没有HCMV视网膜炎的HIV/AIDS患者的细胞毒素细胞毒性途径。第二个目标将确定在女佣期间抑制穿孔蛋白介导的细胞毒性的途径，以使MCMV视网膜炎的易感性。这些实验将集中在女仆中上调的白介素-4上，并被认为将细胞毒性T细胞杀死从主要的穿孔途径转移到主导的FAS/FAS/FASL途径。 第三个目标将确定肿瘤坏死因子A（TNF-A）诱导的凋亡在与女仆相关的MCMV视网膜炎期间介导视网膜组织破坏中的凋亡，并特别注意未感染病毒的视网膜神经元。拟议的研究将提供有关在视网膜疾病进化过程中在视网膜疾病演化中起作用的病毒学，免疫和致病事件的新见解，在逆转录病毒诱导的免疫抑制的独特环境中，需要提供新的诊断策略，以开发新的诊断策略，以更好地预测HIV/HIV疾病患者中HCMV炎的患者的疾病，以更好地促进临床策略的策略，从而在策略中培养了这种策略，以促进这种策略的策略来管理合理的策略。