Role of platelet- monocyte interaction in promoting pro-atherogenic state in HIV-infected individuals

血小板-单核细胞相互作用在促进 HIV 感染者促动脉粥样硬化状态中的作用

• 批准号: 10675056
• 负责人: Meera Vir Singh
• 金额: $ 52.77万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675056
• 关键词: Acceleration; Affect; Aging; Arterial Fatty Streak; Atherosclerosis; Binding; Biology; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Carotid Artery Plaques; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Cholesterol; Chronic; Clinical Research; Clinical Sciences; Complex; Computational Biology; Computer Models; Data; Deposition; Disease; Encapsulated; Endothelial Cells; Event; Exhibits; FCGR3B gene; Feedback; Foam Cells; Gene Expression; Genes; Genetic Transcription; HIV; HIV Infections; HIV-1; Health Status; Human; ITGB3 gene; Image; Immune; Individual; Infection; Inflammation; Inflammatory; Knowledge; Lesion; Link; Lipids; Machine Learning; Macrophage; Maps; Mediating; Metabolic; Metabolic Pathway; MicroRNAs; Modeling; Molecular; Nanotechnology; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Plasma; Platelet Activation; Population; Process; Proteins; Proteomics; Research Infrastructure; Residual state; Risk; Role; Signal Transduction; Small RNA; Source; Statistical Data Interpretation; Statistical Models; Stimulus; Techniques; Testing; Translational Research; Validation; Viral Proteins; Virus Replication; antiretroviral therapy; cardiovascular disorder risk; chemokine; comorbidity; cytokine; early detection biomarkers; epidemiology study; experimental study; immune activation; improved; innovation; interdisciplinary approach; metabolomics; molecular modeling; monocyte; multidisciplinary; network models; novel; particle; predictive modeling; premature; prevent; response; screening; senescence; tool; transcriptome; transcriptome sequencing

Clinical and epidemiological studies have consistently connected HIV infection with increased risk of cardio- vascular disease (CVD). This is due to dysregulated health status associated with residual virus replication, release of soluble viral proteins, and HIV-induced immune activation, which may also be associated with premature immune senescence and persistent inflammation. Chronic inflammation is associated with acceleration of atherosclerosis (AS) and is increasingly prominent among the HIV+ individuals on cART. Monocytes respond to inflammatory stimuli and are precursors of the macrophages within atherosclerotic lesions, including lipid-laden foam cells, and lesion-associated macrophages represent a major source of a number of cytokines and chemokines that direct monocytes into vascular lesions, thus creating a positive- feedback loop. Differentiation of monocytes is enhanced upon interaction with platelets. We and others have shown that platelet-monocyte complexes (PMCs) are increased during HIV infection and CVD. Therefore, we propose to investigate a hypothesis that the PMCs promote atherogenic processes in persons with HIV by triggering monocyte differentiation through horizontal transfer of micro-RNA and protein encapsulated in the platelet-derived microparticles (PMs) to the monocytes and thereafter their interaction with endothelial cells. To test these hypotheses in first aim we define and model molecular networks in monocytes that have or have not interacted with activated platelets in HIV+/- patients with/without carotid plaques using state-of-art CITE-seq. We will employ discrete-state modeling approaches to identify pathways and subnetworks dysregulated in HIV+ individuals with carotid plaques. In second aim, we propose to characterize micro-RNA (miRNA) and proteins encapsulated in platelet-derived microparticles by small-RNA sequencing and proteomics in HIV+/- individuals with/without carotid plaques. The list of miRNAs and proteins will be integrated with the network model from aim 1 to simulate the effect on signaling cascades and their cross-talk. The network model will reveal the role of miRNAs and proteins on the monocyte differentiation into pro-inflammatory phenotype. Additional analysis by machine-learning techniques will allow further prioritization and selection of genes. The ex-vivo experiments will test binding to human carotid endothelial cells and receptiveness of endothelial cells to the differentiated monocytes. In conclusion, our multidisciplinary approach of integrated omics, computational modeling and ex- vivo experiments will reveal mechanisms by which AS is prematurely induced in HIV+ individuals, novel targets to curb AS in HIV+ individuals and biomarkers for early detection of AS. This study holds strong prospects to significantly improve aging related comorbidities in persons living with HIV in general and AS in particular.

临床和流行病学研究一直将HIV感染与心脏风险增加联系 血管疾病（CVD）。这是由于与残留病毒复制相关的健康状况失调， 可溶性病毒蛋白的释放和HIV诱导的免疫激活，这也可能与 过早的免疫衰老和持续性炎症。慢性炎症与 动脉粥样硬化的加速度（AS），在购物车上的HIV+个体中越来越突出。 单核细胞对炎症刺激有反应，并且是动脉粥样硬化中巨噬细胞的前体 病变，包括载有脂质的泡沫细胞和病变相关的巨噬细胞，是A的主要来源 细胞因子和趋化因子的数量将单核细胞直接导致血管病变，从而产生阳性 反馈循环。与血小板相互作用后，单核细胞的分化会增强。我们和其他人有 表明在HIV感染和CVD期间，血小板单细胞复合物（PMC）增加。因此，我们 提议研究PMC在HIV患者中促进动脉粥样硬化过程的假设 通过封装在的微-RNA和蛋白质的水平转移来触发单核细胞分化 血小板衍生的微粒（PMS）到单核细胞，然后与内皮细胞的相互作用。到 在第一个目标中检验这些假设，我们在具有或没有的单核细胞中定义并建模分子网络 使用最先进的Cite-seq与患有/无颈虫的HIV +/-患者中的活化血小板相互作用。我们 将采用离散状态建模方法来识别HIV+中失调的途径和子网 具有颈动脉斑块的人。在第二个目标中，我们建议表征微-RNA（miRNA）和蛋白质 通过小型RNA测序和HIV +/-个体封装在血小板衍生的微粒中 带有/没有颈动脉斑块。 miRNA和蛋白质的列表将与AIM的网络模型集成 1用于模拟对信号级联的影响及其串扰。网络模型将揭示 单核细胞分化为促炎表型的miRNA和蛋白质。其他分析 机器学习技术将允许进一​​步的优先级和基因选择。前体实验将 测试与人类颈动脉内皮细胞的结合以及内皮细胞与分化的接受 单核细胞。总之，我们的综合法学，计算建模和前提的多学科方法 体内实验将揭示其过早诱导的HIV+个体（新目标）的机制 像艾滋病毒+个人和生物标志物一样遏制以供AS早期检测。这项研究具有强大的前景 在一般患有艾滋病毒的患者中，特别是尤其是与衰老相关的合并症。