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Systems Biology of Diffusion Impairment in HIV

HIV扩散损伤的系统生物学

基本信息

批准号：
10188612
负责人：
PANAGIOTIS V BENOS
金额：
$ 77.39万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10188612
关键词：
Address Affect Behavior Therapy Biological Assay Biological Models Carbon Monoxide Caring Cells Chronic Chronic Obstructive Airway Disease Clinical Clinical Data Clinical Pathways Coculture Techniques Communication Complex Coupled Data Data Set Diagnostic radiologic examination Diffuse Diffusion Disease Disease Pathway Endothelial Cells Endothelium Engineering Epithelial Epithelial Cells Exposure to Family Future Gases Gene Expression Genes HIV High-Throughput RNA Sequencing Human Hypoxia Immune Immunologic Deficiency Syndromes Impairment In Vitro Individual Inflammation Inflammatory Response Link Liquid substance Lung Lung Inflammation Lung diseases Mass Spectrum Analysis Measurement Mediating Messenger RNA Metabolic Metabolism Methods MicroRNAs Modeling Molecular Molecular Disease Morbidity - disease rate Oral cavity Outpatients Pathogenesis Pathogenicity Pathway interactions Peripheral Blood Mononuclear Cell Phenotype Physiological Play Population Predisposition Pulmonary Emphysema Pulmonary Hypertension Quality of life Resources Risk Risk Factors Role Sampling Serum Signal Transduction Smoker Smoking Specimen System Systems Biology Testing Therapeutic Time Tissues Vascular Diseases Walking airway obstruction base circulating microRNA cohort disease phenotype endothelial dysfunction experimental study extracellular improved insight loss of function lung microbiome metabolic profile metabolome microbiome mortality network models new therapeutic target non-smoker novel novel therapeutic intervention oral microbiome phenotypic data predictive modeling predictive signature prevent pulmonary function systemic inflammatory response targeted biomarker transcriptome transcriptomics

项目摘要

ABSTRACT Mechanisms of impairment of diffusing capacity for carbon monoxide (DLco), which affects over 50 percent of HIV+ individuals, are poorly understood. No therapies exist despite significant impact on quality of life and mortality. Identifying molecular pathways of DLco impairment in HIV+ individuals and developing ability to predict HIV+ individuals at risk of DLco impairment is thus of utmost importance for improving care. In this proposal, we construct a systems’ modeling approach to identify molecular and clinical pathways contributing to DLco impairment in HIV+ individuals. We collect multiple parallel molecular datasets integrated with detailed pulmonary function, radiographic, and echocardiographic measurements to build a comprehensive, systems- level model of DLco abnormalities in HIV and to develop predictive models of susceptibility to DLco worsening. As our preliminary data suggest that certain miRNAs, such as the hypoxia-induced and metabolically active miR-210, may play an important role in DLco abnormalities in HIV, we then perform hypothesis-testing experiments to determine the impact of miRNAs on lung epithelial and endothelial cells. We utilize our well- phenotyped cohort of over 500 HIV+ individuals with associated biospecimens to execute the following aims: Aim 1: To identify key causal molecular pathways of DLco impairment by integrating clinical features and – omics data from the lung in HIV+ individuals. We will utilize high-throughput RNA sequencing and mass spectrometry to quantify miRNAs, mRNAs, the microbiome, and metabolites in bronchoalveolar fluid and lung epithelial cells in HIV+ individuals with detailed pulmonary function, radiographic, and echocardiographic measurements to construct probabilistic network models of DLco. Key pathways will be validated. Aim 2: To identify predictive signatures of DLco decline from clinical features, transcriptomic, microbiome, and metabolite data in easily accessible clinical specimens. We will build predictive models to identify individuals at risk of developing DLco impairment or having significant decline based on –omics data collected from easily accessible tissues (miRNA and metabolic profiles from serum and PBMCs; microbiome of the oral cavity), coupled with detailed clinical and phenotypic data. Aim 3. To investigate the systems-wide relationship between HIV-induced miRNAs and lung epithelial and endothelial gene reprogramming in HIV+ individuals. Based on our preliminary data, we will test the hypothesis that PBMCs from HIV+ individuals release miRNAs that are delivered to lung epithelial and endothelial cells and consequently regulate gene expression, metabolic function, and activity. These studies investigate an entirely novel paradigm of HIV-mediated communication with pulmonary cells via extracellular miRNA signaling with direct therapeutic relevance as miRNA levels can be modulated by augmentation or inhibition of specific miRNAs. This project will leverage existing resources to identify complex associations and causal relationships in DLco impairment, identify novel therapeutic targets and biomarkers, and improve care of HIV+ individuals.

摘要一氧化碳弥散能力（DLco）受损的机制，影响了50%以上的对艾滋病毒阳性个体知之甚少。尽管对生活质量有显著影响， mortality.鉴定HIV+个体中DLco损伤的分子途径，并培养因此，预测处于DLco损伤风险的HIV+个体对于改善护理至关重要。在这建议，我们构建了一个系统的建模方法，以确定分子和临床途径，与HIV+个体的DLco损伤有关。我们收集了多个平行的分子数据集，肺功能，放射学和超声心动图测量，以建立一个全面的，系统的，水平模型的DLco异常的HIV和开发的预测模型的易感性DLco恶化。我们的初步数据表明，某些miRNAs，如缺氧诱导的和代谢活性的， miR-210可能在HIV的DLco异常中起重要作用，然后我们进行假设检验，实验以确定miRNA对肺上皮细胞和内皮细胞的影响。我们利用我们的优势- 500多名HIV阳性个体的表型队列及相关生物标本，以实现以下目标：目的1：通过整合临床特征和- 来自HIV+个体肺部的组学数据。我们将利用高通量的RNA测序和质量支气管肺泡液和肺中的miRNA、mRNA、微生物组和代谢物具有详细肺功能、放射学和超声心动图的HIV阳性个体中的上皮细胞测量以构建DLco的概率网络模型。将验证关键路径。目标2：从临床特征、转录组学、微生物组和代谢物中鉴定DLco下降预测特征易于获取的临床样本中的数据。我们将建立预测模型，以确定有风险的个人，根据从易受影响的组织学数据，可接近的组织（来自血清和PBMC的miRNA和代谢谱;口腔的微生物组），再加上详细的临床和表型数据。目标3.调查系统范围内的关系在HIV+个体中HIV诱导的miRNAs与肺上皮和内皮基因重编程之间的关系。基于我们的初步数据，我们将检验来自HIV+个体的PBMC释放miRNA的假设，它被输送到肺上皮细胞和内皮细胞，从而调节基因表达，代谢，功能和活动。这些研究调查了一种全新的艾滋病毒介导的传播模式通过细胞外miRNA信号传导与肺细胞发生直接的治疗相关性，因为miRNA水平可以通过增加或抑制特定的miRNA来调节。该项目将利用现有资源，确定DLco损伤中的复杂关联和因果关系，确定新的治疗靶点和生物标志物，并改善对艾滋病毒阳性个体的护理。