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艾滋病毒感染与心血管疾病风险增加联系在一起， 血管疾病（CVD）。这是由于与残留病毒复制相关的失调的健康状态， 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的炎症。慢性炎症与 加速动脉粥样硬化（AS），并且在接受cART的HIV+个体中日益突出。 单核细胞对炎症刺激有反应，是动脉粥样硬化中巨噬细胞的前体 病变，包括载脂泡沫细胞和病变相关的巨噬细胞，是一个主要的来源， 细胞因子和趋化因子的数量，直接单核细胞进入血管病变，从而创造一个积极的， 反馈回路单核细胞的分化在与血小板相互作用后增强。我们和其他人已经 显示血小板-单核细胞复合物（PMCs）在HIV感染和CVD期间增加。所以我们 我建议调查一个假设，即PMC通过以下方式促进HIV感染者的动脉粥样硬化过程： 通过微RNA和包封在微RNA中的蛋白质的水平转移触发单核细胞分化， 血小板衍生的微粒（PM）与单核细胞的相互作用，以及其后它们与内皮细胞的相互作用。到 在First Aim中，我们对单核细胞中的分子网络进行了定义和建模， 使用最先进的CITE-seq，在有/没有颈动脉斑块的HIV+/-患者中与活化的血小板相互作用。我们 将采用离散状态建模方法来识别HIV+中失调的通路和子网络 颈动脉斑块的个体。在第二个目标中，我们提出了表征micro-RNA（miRNA）和蛋白质 在HIV+/-个体中通过小RNA测序和蛋白质组学将其封装在血小板衍生的微粒中 有/无颈动脉斑块。miRNAs和蛋白质的列表将与aim的网络模型集成 1来模拟对信号级联及其串扰的影响。网络模型将揭示 miRNA和蛋白质对单核细胞分化为促炎表型的影响。其他分析 机器学习技术将允许对基因进行进一步的优先排序和选择。体外实验将 测试与人颈动脉内皮细胞的结合和内皮细胞对分化的 单核细胞总之，我们的多学科方法的综合组学，计算建模和前， 体内实验将揭示艾滋病毒阳性个体过早诱导AS的机制， 以遏制艾滋病毒阳性个体的AS和早期检测AS的生物标志物。该研究具有很强的前景， 显著改善艾滋病毒感染者（尤其是AS）的衰老相关合并症。