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

项目总结/摘要 HIV-1（PWH）感染者经历慢性炎症，尽管病毒学 抑制抗逆转录病毒治疗。这些人有很高的药物滥用率， 大麻素具有已知的免疫调节作用。最近的证据表明， NLRP 3炎性体作为炎症的驱动因素。大麻素已被证明可以减少 炎性小体活性。目前尚不清楚的是大麻素对HIV刺激的NLRP 3的影响。 炎性小体活性。我们的目标是阐明大麻素在调节HIV炎性体中的作用， 淋巴组织中的信号传导。这项研究是一个早期研究者医生科学家的建议， 汇集艾滋病毒病毒学、免疫学、受体信号传导和基因组学方面的专业知识，以测试以下目标： 1)确定大麻素治疗对HIV刺激的NLRP 3炎性体信号传导的影响。2)到 鉴定受大麻素处理对HIV刺激的NLRP 3炎性体信号传导影响的细胞类型。第三章 确定大麻素治疗对感染细胞和邻近细胞中炎症信号传导的影响 通过感染扁桃体块的空间转录组学分析。所提出的方法是新颖的，因为它们 利用最近开发的离体人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设施，在山 西奈卫生系统是唯一能够支持这些研究的核心设施，大型患者队列， 和机构支持。西奈山伊坎医学院已证明致力于 这位早期首席研究员的职业发展。目标是发展一个成功的职业生涯， PI作为一名独立的医生科学家，剖析了HIV中大麻素信号传导的发病机制， 1感染和下游炎性体信号传导，目的是找到关键的治疗药物， 治疗HIV-1感染和炎症，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.