Impact of microbiota on AIDS-Kaposi’s sarcoma development and therapy

微生物群对艾滋病-卡波西肉瘤发展和治疗的影响

• 批准号: 10753890
• 负责人: Shou-Jiang Gao
• 金额: $ 79.31万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-08 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753890
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Africa; African; Animal Model; Antibodies; Bacteria; Biology; Blood; CD14 gene; Cell Communication; Cell Proliferation; Cells; Clinical; Clinical Research; Clinical Sciences; Complex; Computational Biology; Data; Development; Disease Outcome; Epidemiology; Flagellin; Gene Expression Profile; Genes; Goals; HIV; HIV Infections; Herpesviridae Infections; Human; Human Herpesvirus 8; Immune; Immune response; Immunocompromised Host; Immunologics; In Situ; Infection; Inflammation; Inflammatory; Innate Immune Response; Kaposi Sarcoma; Laboratories; Lipopolysaccharides; Longitudinal cohort; Machine Learning; Malignant Neoplasms; Methods; Modeling; Molecular; Morbidity - disease rate; Oral; Outcome; Palate Kaposi' s Sarcoma; Pathogenesis; Patients; Population; Poverty; Predictive Factor; Prevention; Preventive; Prognostic Marker; Research Personnel; Role; Societies; Specimen; TLR4 gene; Technology; Therapeutic; Therapeutic Agents; Time; Tobacco use; Translational Research; Underrepresented Populations; Validation; Visceral; Work; antiretroviral therapy; cancer specimen resource; case control; co-infection; cohort; comorbidity; complement pathway; cytokine; dysbiosis; health disparity; innovation; insight; lipopolysaccharide-binding protein; longitudinal analysis; machine learning algorithm; metaplastic cell transformation; microbial; microbiome; microbiota; mortality; novel; pre-clinical; predictive marker; prognostic; prognostic value; response; single cell sequencing; skin organogenesis; statistics; therapeutic target; therapeutically effective; therapy outcome; tumor; tumorigenesis

Project Abstract Microbiota imbalance impacts the development and therapeutic outcome of cancer by altering host immune response and inflammation. Kaposi’s sarcoma (KS) is the most common cancer in HIV-infected patients caused by infection of Kaposi’s sarcoma-associated herpesvirus (KSHV). Despite antiretroviral therapy, KS remains common among HIV-infected patients. It remains unclear what factors might influence the development and therapeutic outcome of AIDS-KS? In response to RFA-CA-22-056 entitled: “Basic/Translational Research on Health Disparities in Underrepresented People Living with HIV (PLWH) and Cancer”, this application specifically addresses the underserved African populations that have high numbers of new HIV infections with the long- term goal is to delineate the pathogenesis of AIDS-associated KS (AIDS-KS), and identify effective therapeutic targets and agents as well as prognostic biomarkers. We have recently shown the impoverishment of oral microbial diversity and enrichment of specific microbiota in oral AIDS-KS, and demonstrated that bacteria and their products lipopolysaccharide and flagellin promote KSHV-induced tumorigenesis by enhancing inflammation in a preclinical KSHV-induced KS animal model. Our hypothesis is that specific microbiota regulates inflammation to impact KS development and therapeutic outcome in AIDS-KS patients. We have assembled a strong collaborative team with diverse expertise in HIV infection, KSHV biology, microbiome, clinical sciences, epidemiology, statistics, computational biology and machine learning. We will take advantage of the long-term clinical studies in Africa with well-defined cross-sectional, case-control and longitudinal cohorts of large HIV-infected and AIDS-KS populations directed by investigators of this project. We will determine the impact of specific microbiota on inflammation and AIDS-KS development by performing case-control analyses in naïve AIDS-KS and HIV/KSHV patients without KS (Aim 1); and examine the impact of specific microbiota on the therapeutic outcome of KS by case-control longitudinal analyses of AIDS-KS patients undergoing anti-retroviral therapy followed by validation analyses in an independent cohort (Aim 2). This interdisciplinary project will analyze the molecular, virological, microbial, immunological, single cell spatial omics, and clinical features of AIDS-KS patients using advanced machine learning approaches. We expect to identify factors that influence the development and therapeutic outcome of AIDS-KS patients. The proposed work is highly significant, and will have prognostic, preventive and therapeutic impacts on AIDS-KS patients. This will be the first time that the role of microbiota will be systematically examined in AIDS-KS patients from well-characterized cohorts. The proposed innovative approaches such as spatial single cell sequencing and machine learning will generate unique and unprecedented results, providing novel insights into the pathogenesis and therapeutic outcome of AIDS-KS.

项目摘要 微生物群失衡通过改变宿主免疫影响癌症的发展和治疗结果 反应和炎症。卡波西肉瘤 (KS) 是 HIV 感染者中最常见的癌症 由卡波西肉瘤相关疱疹病毒（KSHV）感染引起。尽管进行了抗逆转录病毒治疗，KS 仍然存在 常见于 HIV 感染者。目前尚不清楚哪些因素可能影响其发展和 AIDS-KS的治疗结果？回应题为“基础/转化研究”的 RFA-CA-22-056 代表性不足的艾滋病毒感染者 (PLWH) 和癌症患者的健康差异”，该申请特别指出 解决服务不足的非洲人口的问题，这些人口有大量新发艾滋病毒感染者，而且长期 术语目标是描述艾滋病相关 KS (AIDS-KS) 的发病机制，并确定有效的治疗方法 靶点和药物以及预后生物标志物。我们最近已经证明了口语的贫乏 口腔 AIDS-KS 中的微生物多样性和特定微生物群的富集，并证明细菌和 他们的产品脂多糖和鞭毛蛋白通过增强炎症促进 KSHV 诱导的肿瘤发生 在临床前 KSHV 诱导的 KS 动物模型中。我们的假设是特定的微生物群调节 炎症影响 AIDS-KS 患者的 KS 发展和治疗结果。我们有 组建了一支强大的协作团队，在 HIV 感染、KSHV 生物学、微生物组、临床 科学、流行病学、统计学、计算生物学和机器学习。我们将利用 在非洲进行的长期临床研究，具有明确的横断面、病例对照和纵向队列研究 本项目研究人员指导的 HIV 感染者和 AIDS-KS 人群。我们将确定影响 通过在幼稚环境中进行病例对照分析，了解特定微生物群对炎症和 AIDS-KS 发展的影响 AIDS-KS 和无 KS 的 HIV/KSHV 患者（目标 1）；并检查特定微生物群对 通过对接受抗逆转录病毒治疗的 AIDS-KS 患者进行病例对照纵向分析来了解 KS 的治疗结果 治疗后在独立队列中进行验证分析（目标 2）。这个跨学科项目将 分析分子、病毒学、微生物、免疫学、单细胞空间组学和临床特征 使用先进的机器学习方法治疗 AIDS-KS 患者。我们希望找出影响因素 AIDS-KS 患者的发展和治疗结果。拟议的工作非常重要，并将 对 AIDS-KS 患者具有预后、预防和治疗作用。这将是该角色首次亮相 将对来自特征明确的队列的 AIDS-KS 患者的微生物群进行系统检查。拟议的 空间单细胞测序和机器学习等创新方法将产生独特且 前所未有的结果，为 AIDS-KS 的发病机制和治疗结果提供了新的见解。