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.

 描述（由适用提供）：与艾滋病相关的人类巨细胞病毒（HCMV）视网膜炎会导致HIV-免疫抑制的患者的视力丧失和失明，这些患者无法获得联合抗逆转录病毒疗法（CART）或未能遵守或不遵守或响应购物车。因此，与AIDS相关的HCMV视网膜炎仍然是全球重大的眼科问题。在提高我们诊断，预防和/或治疗IADS相关的HCMV视网膜炎的能力方面取得进展的关键障碍是对HCMV（人类HCMV）的机制的理解，该机制是人类IS疱疹病毒，导致视网膜组织在发病和与AIDS相关HCMV视网膜炎的发作期间导致视网膜组织破坏。我们的目标是通过获得与建立抑制细胞因子信号1（SOCS1），SOCS3，坏死性和凋亡在与艾滋病相关的HCMV视网膜炎的病原体中所需的相对作用来解决与AIDS相关的HCMV视网膜炎的问题以及进步的关键障碍。我们的中心假设是，SOCS1，SOCS3，坏死性和凋亡通过不同的机制单独巩固，在与AIDS相关的HCMV视网膜炎的发病机理期间共同促进视网膜组织破坏。我们的目标是使用逆转录病毒诱导的免疫抑制（女仆）的小鼠中的小鼠小鼠（MCMV）视网膜炎的成熟且与临床相关的动物模型，以及（1）在体外细胞培养方法上以及（1）获得所需的信息所需的信息，从而在33期间贡献了SOCS1，necroptsisssiss，并获得了所需的信息。与女仆相关的MCMV视网膜炎的进化，以及（2）使用此信息来证明，在与艾滋病相关的HCMV期间，这些目标在成功完成三个特定目标时也可以实现这些目标，这也可以实现：（1）测试SOCS1和SOCS3蛋白在McMAids-RAIDS-RAIDS-RAIDS-RAIDS-RAIDS-RAIDESS中起着重要的作用，以实现三个具体目标：（1）坏死性和凋亡在与女仆相关的MCMV视网膜炎的发病机理中起着重要作用，（3）检验了HCMV刺激SOCS1，SOCS3，坏死性和热吞作用的假说。我们的预期结果将包括（1）MCMV通过对SOCS1和SOCS3蛋白的眼内模拟来促进残留的组织破坏，从而干扰JAK/STAT途径和/或TOLL样受体（TLR）信号（TLR）信号（TLR）信号（TLR）对抑制I型抗病毒型I型McMM MCMV的触发（2）促进型号（2）促进型号（2）其中包括坏死性和凋亡以及凋亡，（3）HCMV通过SOCS1，SOCS3，坏死病和热吞作用机制促进与AIDS相关的HCMV视网膜炎期间的视网膜组织破坏。对与AIDS相关的HCMV视网膜炎研究的影响将包括可能直接或间接导致与AIDS相关的HCMV视网膜炎以及疱疹病毒起源的其他视网膜疾病的新型治疗方法的新信息。