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

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
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-15 至 2020-05-31

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中文摘要
翻译
抽象的。尽管接受了有效的抗逆转录病毒治疗,但艾滋病毒感染者仍处于... 患慢性阻塞性肺疾病的风险增加,表现为肺气肿,发病率高于 一般人口发展的年龄较早。基于对第一个病理学的认识 慢性阻塞性肺疾病的表现在小气道上皮(SAE),这种肺破坏表现为- 特征性肺气肿始于SAE周围的肺泡,初步数据显示 气道基底部干/祖细胞(BC)能够表达多种破坏性蛋白。 AS是呼吸道BC的亚群,表达HIV受体,HIV可诱导BC上调EX-受体。 通过触发HSPG2受体抑制和释放基质金属蛋白酶9 ERK和AKT通路,我们假设人类小气道BC的某些亚群 有HIV的受体,由于与HIV的相互作用,这些BC亚群是 在病理上重新编程以获得一种“组织破坏性”表型,该表型可引发局部 肺泡破坏。为了评估这一假设,我们提出了三个目标。目标1.评估- 假设人类小气道BC亚群具有HIV受体,并且 艾滋病病毒可以与这些BC亚群相互作用并重新编程。根据初步数据, HIV将结合到BC,但不会在BC中复制,使用单细胞RNA测序和FACS分选,我们将 识别和表征易感BC人群和特定BC HIV受体。目标2. 为了检验这一假设,作为HIV相互作用的结果,呼吸道BC亚群是致病的。 在逻辑上重新编程,以获得一种“组织破坏性”表型,能够启动 必要的组织破坏,这些过程被香烟烟雾夸大了。我们- 在相关的BC亚群中,单独或在有香烟烟雾的情况下,研究将是汽车- 目的:鉴定HIV诱导的BC“组织破坏性”表型,鉴定其特异性受体。 通过HIV结合激活BC中的Tors和途径,并证明这些途径的抑制- Ways将使BC的“组织破坏性”表型恢复正常。目标3.调查假说- 艾滋病毒携带者的呼吸道BC,在更大程度上,是吸烟者的呼吸道BC, 在体内获得了一种“破坏组织”的表型,并且这个过程在 用高效抗逆转录病毒疗法治疗艾滋病毒。为了验证体外研究的有效性, AIMS 1-2,通过支气管镜和刷检HIV+SAE恢复气道BC(未控制和 非吸烟者和吸烟者的“组织破坏性”表型将被评估。 与可比的艾滋病毒‾患者进行比较,并确定这种表型是否可以通过 相关的通路抑制剂。
英文摘要
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.
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  • 批准号:
    10481279
  • 项目类别:
  • 资助金额:
    $30.0万
  • 财政年份:
    2022
  • 负责人:
    RONALD G CRYSTAL
  • 依托单位:
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