HIV Reprogrammed Airway Basal Cells Acquire a “Tissue Destructive” Phenotype

HIV重编程的气道基底细胞获得“组织破坏性”表型

• 批准号: 9204585
• 负责人: RONALD G CRYSTAL
• 金额: $ 83.87万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204585
• 关键词: Acceleration; Adverse effects; Age; Aging; Alveolar Macrophages; Alveolus; Anti-Retroviral Agents; Antiviral Therapy; Basal Cell; Basal Cell Hyperplasia; Binding; Bronchoscopy; CD8B1 gene; Cells; Chronic; Chronic Obstructive Airway Disease; Comorbidity; Connective Tissue; Data; Development; Disease; Gelatinase B; General Population; HIV-1; Highly Active Antiretroviral Therapy; Human; In Vitro; Incidence; Individual; Infection; Intravenous; Knowledge; Life; Link; Lung; Modeling; Opportunistic Infections; Pathologic; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Play; Pneumocystis carinii; Population; Process; Proto-Oncogene Proteins c-akt; Pulmonary Emphysema; Recording of previous events; Risk; Role; Secondary to; Smoke; Smoker; Sorting - Cell Movement; Stem cells; Structure of parenchyma of lung; T-Lymphocyte; Tissues; abstracting; airway epithelium; alpha 1-Antitrypsin Deficiency; alveolar destruction; base; cigarette smoking; cigarette smoking; in vivo; inhibitor/antagonist; non-smoker; novel; receptor; stem; transcriptome sequencing

Abstract. Despite treatment with effective anti-retroviral therapy, HIV-infected individuals are at in- creased risk for the development of COPD, manifesting as emphysema, with a higher incidence than the general population developing at an earlier age. Based on the knowledge that the first pathologic manifestations of COPD are in the small airway epithelium (SAE), that the lung destruction that char- acterizes emphysema begins in the alveoli surrounding the SAE and preliminary data demonstrating that airway basal stem/progenitor cells (BC) are capable of expressing a variety of destructive prote- ases, subsets of airway BC express HIV receptors, and that HIV can induce BC to up-regulate ex- pression and release of matrix metalloproteinase (MMP) 9 via triggering the HSPG2 receptors and ERK and AKT pathways, we hypothesize that there are subsets of human small airway BC that have receptors for HIV, and consequent to the interaction with HIV, these BC subsets are pathologically reprogrammed to acquire a “tissue destructive” phenotype that initiates local alveolar destruction. To evaluate this hypothesis, we propose 3 aims. Aim 1. To assess the hy- pothesis that subsets of the population of human small airway BC have receptors for HIV, and that HIV can interact with and reprogram these BC subpopulations. Based on preliminary data, HIV will bind to, but not replicate in BC, using single cell RNA sequencing and FACS sorting, we will identify and characterize the susceptible BC populations and the specific BC HIV receptors. Aim 2. To examine the hypothesis that, consequent to HIV interaction, airway BC subsets are patho- logically reprogrammed to acquire a “tissue destructive” phenotype, capable of initiating con- nective tissue destruction, and that these processes are exaggerated by cigarette smoke. Us- ing the relevant BC subpopulations, alone or in the presence of cigarette smoke, studies will be car- ried out to characterize the HIV-induced BC “tissue destructive” phenotype, identify the specific recep- tors and pathways in BC activated by HIV binding, and to demonstrate that inhibition of these path- ways will return the BC “tissue destructive” phenotype to normal. Aim 3. To investigate the hypoth- esis that airway BC of HIV+ individuals, and to greater extent, HIV+ individuals that smoke, have acquired a “tissue destructive” phenotype in vivo, and that this process continues after HIV treatment with highly active anti-retroviral therapy. To validate the in vitro studies in aims 1-2, airway BC recovered by bronchoscopy and brushing of the SAE of HIV+ (uncontrolled and controlled) of nonsmokers and smokers will be assessed for the “tissue destructive” phenotype com- pared to comparable HIV‾ individuals, and determine whether this phenotype can be reversed with relevant pathway inhibitors.

抽象。尽管接受了有效的抗逆转录病毒疗法，艾滋病毒感染者仍处于- COPD的发展风险增加，表现为肺气肿，发病率高于 一般人口在较早的年龄发展。基于第一个病理性的 COPD的表现是在小气道上皮细胞（SAE）中，即， 表征肺气肿开始于SAE周围的肺泡，初步数据表明 气道基底干/祖细胞（BC）能够表达多种破坏性蛋白， 气道BC的亚群表达HIV受体，HIV可诱导BC上调表达， 通过触发HSPG 2受体表达和释放基质金属蛋白酶（MMP）9， ERK和AKT通路，我们假设存在人类小气道BC的亚群， 具有HIV受体，并且由于与HIV的相互作用，这些BC亚群 病理性重编程以获得“组织破坏性”表型， 肺泡破坏为了评估这个假设，我们提出了三个目标。目标1.为了评估hy- 假设人小气道BC群体的亚群具有HIV受体，和 艾滋病毒可以与这些BC亚群相互作用并重新编程。根据初步数据， HIV将与BC结合，但不会在BC中复制，使用单细胞RNA测序和FACS分选，我们将 确定和表征易感BC人群和特定BC HIV受体。目标2. 为了检验这一假设，即由于HIV相互作用，气道BC亚群是病理性的， 逻辑上重新编程以获得“组织破坏性”表型，能够启动连接， 坏死组织的破坏，这些过程被香烟烟雾夸大。我们- 在相关的BC亚群中，单独或在香烟烟雾存在的情况下，研究将是： 为了表征HIV诱导的BC“组织破坏性”表型，确定特异性受体， 通过HIV结合激活BC中的受体和途径，并证明抑制这些途径- 方法将使BC“组织破坏性”表型恢复正常。目标3.去调查那个假设- 结论是HIV阳性个体的气道BC，在更大程度上，吸烟的HIV阳性个体， 在体内获得了“组织破坏性”表型，并且该过程在 采用高效抗逆转录病毒疗法治疗艾滋病毒。为了验证体外研究， 目的1-2，通过支气管镜检查和刷拭治疗HIV+ SAE（未控制和 控制）的非吸烟者和吸烟者的“组织破坏性”表型COM- 与可比较的HIV感染者进行比较，并确定这种表型是否可以逆转， 相关通路抑制剂。