Elucidating the mechanisms of cannabinoids on HIV-1 infection and inflammasome activation

项目摘要/摘要 感染HIV-1(PWH)的人会经历慢性炎症，尽管从病毒学角度来看，这会导致共病 抑制抗逆转录病毒治疗。这些人有很高的药物滥用比率，包括 已知具有免疫调节作用的大麻素。最近的证据表明， NLRP3炎症体作为炎症的驱动因素。大麻类物质已被证明可以减少 炎性小体活动。目前尚不清楚的是，大麻类物质对艾滋病毒刺激的NLRP3有什么影响 炎性小体活动。我们的目标是阐明大麻素在调节HIV-炎症小体中的作用 淋巴组织中的信号。这项研究是由一位早期研究员内科科学家提出的，他将 汇集艾滋病毒病毒学、免疫学、受体信号传递和基因组学方面的专业知识，以测试以下目标： 1)研究大麻素对HIV刺激的NLRP3炎症信号转导通路的影响。2)至 确定大麻素处理对HIV刺激的NLRP3炎症信号的影响的细胞类型。3) 确定大麻素治疗对感染细胞和邻近细胞炎症信号的影响 通过对感染的扁桃体块进行空间转录分析。提出的方法是新颖的，因为它们 利用最近开发的体外人类扁桃体感染模型和单细胞成像和基因表达 该平台将允许了解与HIV-1感染相关的炎症信号 单细胞水平。研究人员和合作者提供免费的专业知识和山上的设施 西奈卫生系统是唯一有能力支持这些研究的核心设施，大型患者队列， 和制度支持。位于西奈山的伊坎医学院已经表明了对 这位早期首席调查员的职业发展。我们的目标是发展一个成功的职业生涯 作为一名独立的内科科学家，PI剖析了艾滋病毒中大麻素信号的发病机制-- 1感染和下游炎症体信号转导，目标是在 HIV-1感染和炎症的治疗以及了解慢性炎症和 滥用药物。

PROJECT SUMMARY/ABSTRACT People with HIV-1 (PWH) experience chronic inflammation that leads to comorbidities despite virological suppression on anti-retroviral therapy. These individuals have high rates of substance abuse including cannabinoids which have known immunomodulatory effects. Recent evidence has suggested an important role of the NLRP3 inflammasome as a driver of inflammation. Cannabinoids have been shown to reduce inflammasome activity. What remains unknown is the effect that cannabinoids have on HIV-stimulated NLRP3 inflammasome activity. Our goal is to elucidate the role of cannabinoids in modulating HIV-inflammasome signaling in lymphoid tissue. This study is the proposal of an early stage investigator physician scientist who will bring together expertise in HIV virology, immunology, receptor signaling, and genomics to test the following aims: 1) To determine the effect of cannabinoid treatment on HIV-stimulated NLRP3 inflammasome signaling. 2) To identify the cell types impacted by cannabinoid treatment on HIV-stimulated NLRP3 inflammasome signaling. 3) To identify the impact of cannabinoid treatment on inflammatory signaling in infected and neighboring cells through spatial transcriptomic analysis of infected tonsil blocks. The methods proposed are novel in that they utilize a recently developed ex vivo human tonsil infection model and a single cell imaging and gene expression platform that will allow for understanding the inflammatory signaling that is associated with HIV-1 infection on a single cell level. The investigators and collaborators offer complimentary expertise and the facilities at the Mount Sinai Health System are uniquely capable of supporting these studies with core facilities, large patient cohorts, and institutional support. The Icahn School of Medicine at Mount Sinai has demonstrated commitment to the career development of this early stage principal investigator. The goal is to develop a successful career of the PI as an independent physician scientist in dissecting out the pathogenesis of the cannabinoid signaling in HIV- 1 infection and downstream inflammasome signaling with the goal of finding key therapeutic agents in the treatment of HIV-1 infection and inflammation and in understanding the interplay of chronic inflammation and drugs of abuse.