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.

抽象的一氧化碳 (DLco) 扩散能力受损的机制，影响超过 50% 尽管对艾滋病病毒感染者的生活质量和生活质量有重大影响，但目前尚无治疗方法。确定 HIV+ 个体 DLco 损伤的分子途径并培养降低死亡率的能力。因此，预测有 DLco 损伤风险的 HIV+ 个体对于改善护理至关重要。建议，我们构建了一个系统建模方法来识别分子和临床途径我们收集了多个平行分子数据集，并整合了详细信息。肺功能、放射线照相和超声心动图测量，以建立一个全面的系统 HIV 中 DLco 异常的水平模型，并开发 DLco 恶化易感性的预测模型。正如我们的初步数据表明，某些 miRNA，例如缺氧诱导的和代谢活跃的 miRNA miR-210可能在HIV DLco异常中发挥重要作用，然后我们进行假设检验我们利用我们的良好实验来确定 miRNA 对肺上皮细胞和内皮细胞的影响。对超过 500 名 HIV+ 个体以及相关生物样本进行表型分析，以实现以下目标：目标 1：通过整合临床特征和 – 来确定 DLco 损伤的关键因果分子途径 - 我们将利用高通量 RNA 测序和质谱数据。光谱法定量支气管肺泡液和肺中的 miRNA、mRNA、微生物组和代谢物 HIV+ 个体的上皮细胞，具有详细的肺功能、放射线检查和超声心动图检查构建 DLco 概率网络模型的测量将得到验证目标 2：从临床特征、转录组、微生物组和代谢物中识别 DLco 下降的预测特征我们将建立预测模型来识别有风险的个体。根据轻松收集的组学数据，出现 DLco 损伤或显着下降可接近的组织（来自血清和 PBMC 的 miRNA 和代谢特征；口腔微生物组），结合详细的临床和表型数据。目标 3. 研究全系统的关系。 HIV+个体中HIV诱导的miRNA与肺上皮和内皮基因重编程之间的关系。根据我们的初步数据，我们将检验 HIV+ 个体的 PBMC 释放 miRNA 的假设被递送至肺上皮细胞和内皮细胞，从而调节基因表达、代谢这些研究调查了艾滋病毒介导的交流的全新范式。通过细胞外 miRNA 信号转导与肺细胞相互作用，具有直接的治疗相关性，因为 miRNA 水平可以通过增强或抑制特定 miRNA 进行调节该项目将利用现有资源识别 DLco 损伤的复杂关联和因果关系，确定新的治疗靶点和生物标志物，并改善对艾滋病病毒感染者的护理。