Cytomegalovirus retinitis pathogenesis: Mechanisms of retinal tissue destruction

巨细胞病毒视网膜炎发病机制：视网膜组织破坏机制

• 批准号: 9070590
• 负责人: Richard D Dix
• 金额: $ 37万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9070590
• 关键词: Acquired Immunodeficiency Syndrome; Address; Animal Model; Antiviral Agents; Apoptosis; Blindness; CASP1 gene; CISH gene; Caspase; Cell Culture Techniques; Cell Death; Cells; Coupled; Cytomegalovirus; Cytomegalovirus Retinitis; Development; Diagnosis; Evolution; Eye; Goals; HIV; Herpesviridae; Human; Human Cell Line; Immunosuppression; In Vitro; Inflammatory; Interferon Type I; Interferons; Interleukin-1; Interleukin-18; Interleukin-6; Lead; Messenger RNA; Mission; Murid herpesvirus 1; Murine Acquired Immunodeficiency Syndrome; Mus; Outcome; Pathogenesis; Pathway interactions; Patients; Performance; Play; Production; Proteins; Public Health; RIPK1 gene; Receptor Signaling; Research; Retinal; Retinal Diseases; Retinitis; Retroviridae; Role; Series; Signaling Protein; Testing; Time; Tissues; Toll-like receptors; Up-Regulation; Virus; Vision; Work; antiretroviral therapy; clinically relevant; cytokine; killings; meetings; novel therapeutic intervention; prevent; public health relevance

 DESCRIPTION (provided by applicant): AIDS-related human cytomegalovirus (HCMV) retinitis causes vision loss and blindness in HIV-immuno- suppressed patients who do not have access to combination antiretroviral therapy (cART) or who fail to adhere to or respond to cART. AIDS-related HCMV retinitis therefore remains a significant ophthalmologic problem worldwide. A critical barrier to progress in advancing our ability to diagnose, prevent, and/or treat AIDS- related HCMV retinitis is an absence of an understanding of the mechanisms by which HCMV, a human  herpesvirus, causes retinal tissue destruction during onset and progression of AIDS-related HCMV retinitis. Our goal is to address the problem of AIDS-related HCMV retinitis and the critical barrier to progress by obtaining the information needed to establish the relative role of suppressor of cytokine signaling 1 (SOCS1), SOCS3, necroptosis, and pyroptosis in the pathogenesis of AIDS-related HCMV retinitis. Our central hypothesis is that SOCS1, SOCS3, necroptosis, and pyroptosis individually conspire via different mechanisms to contribute collectively to retinal tissue destruction during the pathogenesis of AIDS-related HCMV retinitis. Our objectives are to use a well-established and clinically relevant animal model of mouse cytomegalovirus (MCMV) retinitis in mice with retrovirus-induced immunosuppression (MAIDS) coupled with in vitro cell culture approaches to (1) obtain the information needed to understand the mechanisms by which SOCS1, SOCS3, necroptosis, and pyroptosis contribute to retinal tissue destruction during evolution of MAIDS-related MCMV retinitis, and (2) use this information to demonstrate that these mechanisms of retinal tissue destruction also operate during AIDS-related HCMV retinitis. These objectives will be met through successful completion of three Specific Aims: (1) test the hypothesis that SOCS1 and SOCS3 proteins play a significant role in the pathogenesis of MAIDS-related MCMV retinitis, (2) test the hypothesis that necroptosis and pyroptosis play a significant role in the pathogenesis of MAIDS-related MCMV retinitis, and (3) test the hypothesis that HCMV stimulates SOCS1, SOCS3, necroptosis, and pyroptosis during AIDS-related HCMV retinitis. Our expected outcomes will include establishing that (1) MCMV promotes retinal tissue destruction through intraocular stimulation of SOCS1 and SOCS3 proteins that interfere with the JAK/STAT pathway and/or toll-like receptor (TLR) signaling to dampen antiviral Type I  interferon (IFN) production, (2) MCMV promotes retinal tissue destruction through intraocular stimulation of multiple cell death pathways that include necroptosis and pyroptosis as well as apoptosis, and (3) HCMV promotes retinal tissue destruction during AIDS-related HCMV retinitis via SOCS1, SOCS3, necroptosis, and pyroptosis mechanisms. The impact on the field of AIDS-related HCMV retinitis research will include new information that could directly or indirectly lead to novel therapeutic approaches for management of AIDS-related HCMV retinitis as well as other retinal diseases of herpesvirus origin.