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: 10545633
• 负责人: Meera Vir Singh
• 金额: $ 54.3万
• 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/10545633
• 关键词: Acceleration; Affect; Aging; Arterial Fatty Streak; Atherosclerosis; Binding; Biology; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; 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; Disease Management; Encapsulated; Endothelial Cells; Event; Exhibits; FCGR3B gene; Feedback; Foam Cells; Genes; Genetic Transcription; HIV; HIV Infections; HIV-1; Health Status; Human; ITGB3 gene; Image; Immune; Individual; Infection; Inflammation; Inflammatory; Institutes; Knowledge; Lesion; Link; Lipids; Machine Learning; 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; macrophage; metabolomics; molecular modeling; monocyte; multidisciplinary; network models; novel; 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脏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健康状态， 可溶病毒蛋白的释放，以及艾滋病毒诱导的免疫激活，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(AS)的加速，在服用CART的HIV+患者中日益突出。 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细胞 病变，包括富含脂质的泡沫细胞和病变相关的巨噬细胞是 引导单核细胞进入血管病变的细胞因子和趋化因子的数量，从而产生积极的- 反馈环路。单核细胞的分化在与血小板相互作用时得到增强。我们和其他人有 研究表明，在HIV感染和心血管疾病期间，血小板-单核细胞复合体(PMCs)增加。因此，我们 建议调查一种假说，即PMC通过以下方式促进艾滋病毒感染者的动脉粥样硬化过程 通过水平转移包裹在细胞内的微小RNA和蛋白质来触发单核细胞分化 血小板衍生的微粒(PM)进入单核细胞，然后与内皮细胞相互作用。至 测试这些假设的首要目的是定义和模拟单核细胞中有或没有分子网络 使用最先进的CITE-SEQ技术与有/无颈动脉斑块的HIV+/-患者激活的血小板相互作用。我们 将使用离散状态建模方法来识别在HIV+中调节失调的途径和子网络 有颈动脉斑块的个体。在第二个目标中，我们建议对微型rna(Mirna)和蛋白质进行表征。 用小RNA测序和蛋白质组学研究HIV+/-患者的血小板衍生微粒 有/没有颈动脉斑块。MiRNAs和蛋白质的列表将与AIM的网络模型相结合 1模拟信号级联及其串扰的影响。网络模型将揭示 MiRNAs和蛋白质对单核细胞分化为促炎表型的影响。作者补充分析 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 人颈动脉内皮细胞结合力及内皮细胞对分化细胞的感受性 单核细胞。总而言之，我们整合了组学、计算建模和前处理的多学科方法。 活体实验将揭示在HIV+个体中过早诱发AS的机制，新的靶点 遏制人类免疫缺陷病毒携带者的AS和早期检测AS的生物标志物。这项研究具有很强的前景 显着改善艾滋病毒携带者，特别是AS患者与衰老有关的合并症。