Cytomegalovirus retinitis pathogenesis: Mechanisms of retinal tissue destruction

巨细胞病毒性视网膜炎发病机制：视网膜组织破坏机制

• 批准号: 8886844
• 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 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886844
• 关键词: Acquired Immunodeficiency Syndrome; Address; Animal Model; Antiviral Agents; Apoptosis; Blindness; CISH gene; Caspase; Caspase-1; 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; Receptor Signaling; Relative (related person); 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（由申请人提供）：艾滋病相关的人类巨细胞病毒（HCMV）视网膜炎会导致无法接受联合抗逆转录病毒治疗（cART）或未能坚持或对 cART 做出反应的 HIV 免疫抑制患者视力丧失和失明。因此，艾滋病相关的 HCMV 视网膜炎仍然是世界范围内一个重要的眼科问题。在提高我们诊断、预防和/或治疗艾滋病相关的 HCMV 视网膜炎的能力方面取得进展的一个关键障碍是缺乏对 HCMV（一种人类疱疹病毒）在艾滋病相关的 HCMV 视网膜炎的发作和进展过程中引起视网膜组织破坏的机制的了解。我们的目标是通过获取确定细胞因子信号传导抑制因子 1 (SOCS1)、SOCS3、坏死性凋亡和细胞焦亡在 AIDS 相关 HCMV 视网膜炎发病机制中的相对作用所需的信息，解决 AIDS 相关 HCMV 视网膜炎的问题和进展的关键障碍。我们的中心假设是，在 AIDS 相关 HCMV 视网膜炎的发病过程中，SOCS1、SOCS3、坏死性凋亡和焦亡分别通过不同机制共同导致视网膜组织破坏。我们的目标是在逆转录病毒诱导的免疫抑制 (MAIDS) 小鼠中使用成熟且具有临床相关性的小鼠巨细胞病毒 (MCMV) 视网膜炎动物模型，并结合体外细胞培养方法，以 (1) 获得所需的信息，以了解 SOCS1、SOCS3、坏死性凋亡和焦亡在视网膜组织破坏过程中的作用机制。 MAIDS 相关 MCMV 视网膜炎的演变，以及 (2) 使用此信息来证明这些视网膜组织破坏机制也在 AIDS 相关 HCMV 视网膜炎期间发挥作用。这些目标将通过成功完成三个具体目标来实现：(1) 检验 SOCS1 和 SOCS3 蛋白在 MAIDS 相关 MCMV 视网膜炎的发病机制中发挥重要作用的假设，(2) 检验坏死性凋亡和焦亡在 MAIDS 相关 MCMV 视网膜炎的发病机制中发挥重要作用的假设，以及 (3) 检验 HCMV 的假设 在 AIDS 相关的 HCMV 视网膜炎期间刺激 SOCS1、SOCS3、坏死性凋亡和细胞焦亡。我们的预期结果将包括确定 (1) MCMV 通过眼内刺激 SOCS1 和 SOCS3 蛋白促进视网膜组织破坏，这些蛋白干扰 JAK/STAT 通路和/或 Toll 样受体 (TLR) 信号传导，抑制抗病毒 I 型 α 干扰素 (IFN) 的产生，(2) MCMV 通过眼内刺激多个细胞死亡来促进视网膜组织破坏 (3) HCMV 在 AIDS 相关的 HCMV 视网膜炎期间通过 SOCS1、SOCS3、坏死性凋亡和焦亡机制促进视网膜组织破坏。对艾滋病相关 HCMV 视网膜炎研究领域的影响将包括新信息，这些新信息可能直接或间接导致治疗艾滋病相关 HCMV 视网膜炎以及疱疹病毒起源的其他视网膜疾病的新治疗方法。