Fibrocytes in human pulmonary fibrosis

人肺纤维化中的纤维细胞

基本信息

  • 批准号:
    8791329
  • 负责人:
  • 金额:
    $ 54.17万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-03-01 至 2017-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is an illness characterized by progressive decline in lung function and premature death from respiratory failure. There is currently no effective therapy for this disease and the study of new therapeutic options is hampered by our inability to predict patients at risk for clinical deterioration. Fibrocytes are a novel population of bone marrow-derived circulating progenitor cells that have been shown to traffic to the lungs and contribute to fibrosis in animal models of pulmonary fibrosis, and whose numbers correlate with the degree of fibrosis and with survival in human pulmonary fibrosis. Our broad, long-term objective is to understand the contribution of fibrocytes to human pulmonary fibrosis and to target this pathological mechanism as a therapeutic modality. Our preliminary data show that: 1) as compared to healthy controls, patients with fibrotic interstitial lung disease have markedly increased levels of the fibrocyte-attracting chemokine, CXCL12, in both the lungs and plasma, which is associated with a marked elevation in the number of peripheral blood and lung fibrocytes; 2) patients with Hermansky-Pudlak syndrome, a genetic disorder that universally results in pulmonary fibrosis in the 3rd decade of life, have a similar expansion of the circulating fibrocyte pool; 3) The elevation of circulating fibrocyte count is an independent predictor of death in IPF; 4) CXCR4 is the major chemokine receptor expressed on human fibrocytes, and its expression is down-regulated by the mTOR inhibitor, sirolimus; and 5) in an animal model of pulmonary fibrosis, administration of sirolimus results in reduced number of blood and lung fibrocytes as well as reduced lung fibrosis. Our overall hypothesis is that in patients with pulmonary fibrosis, 1) the number and/or phenotype of circulating fibrocytes identify patients at risk of disease progression before the progression is detectable clinically, and 2) therapy with the mTOR inhibitor, sirolimus, reduces the number of circulating fibrocytes. We propose to test this hypothesis under the following specific aims: 1) To determine the predictive value of the number and phenotype of circulating fibrocytes for development and progression of pulmonary fibrosis in a cohort of patients with Hermansky-Pudlak syndrome. 2) To serially correlate the number and phenotype of circulating fibrocytes to conventional indices of disease severity in patients with idiopathic pulmonary fibrosis. 3) To perform a short-term pilot trial of the mTOR inhibitor, sirolimus, in patients with IPF to determine its effect on the number and phenotype of circulating fibrocytes. The significance of the proposed studies is that they have the potential to identify a novel biomarker to predict disease progression in IPF, and to lay the groundwork for a therapy for this illness that targets fibrocytes.
描述(由申请方提供):特发性肺纤维化(IPF)是一种以肺功能进行性下降和呼吸衰竭导致的过早死亡为特征的疾病。目前对这种疾病没有有效的治疗方法,新的治疗选择的研究受到我们无法预测临床恶化风险的患者的阻碍。纤维细胞是一种新的骨髓来源的循环祖细胞群体,其已被证明运输到肺并在肺纤维化的动物模型中促成纤维化,并且其数量与纤维化程度和人肺纤维化中的存活率相关。我们广泛的长期目标是了解纤维细胞对人类肺纤维化的贡献,并将这种病理机制作为治疗方式。我们的初步数据显示:1)与健康对照相比,纤维化间质性肺病患者在肺和血浆中具有显著增加的纤维细胞吸引趋化因子CXCL 12水平,其与外周血和肺纤维细胞数量的显著升高相关; 2)患有Hermansky-Pudlak综合征(一种普遍导致30岁以下肺纤维化的遗传性疾病)的患者具有类似的循环纤维细胞池的扩张; 3)循环纤维细胞计数的升高是IPF中死亡的独立预测因子; 4)CXCR 4是在人纤维细胞上表达的主要趋化因子受体,并且其表达被mTOR抑制剂西罗莫司下调;和5)在肺纤维化的动物模型中,西罗莫司的施用导致血液和肺纤维细胞的数量减少以及肺纤维化减少。我们的总体假设是,在肺纤维化患者中,1)循环纤维细胞的数量和/或表型在临床上可检测到进展之前识别处于疾病进展风险的患者,和2)用mTOR抑制剂西罗莫司治疗减少循环纤维细胞的数量。我们提出在以下具体目标下检验这一假设:1)确定循环纤维细胞的数量和表型对Hermansky-Pudlak综合征患者队列中肺纤维化发展和进展的预测价值。2)特发性肺纤维化患者循环纤维细胞的数量和表型与疾病严重程度的常规指标之间的系列相关性。3)在IPF患者中进行mTOR抑制剂西罗莫司的短期初步试验,以确定其对循环纤维细胞数量和表型的影响。拟议研究的意义在于,它们有可能确定一种新的生物标志物来预测IPF的疾病进展,并为靶向纤维细胞的这种疾病的治疗奠定基础。

项目成果

期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
M-CSF Mediates Host Defense during Bacterial Pneumonia by Promoting the Survival of Lung and Liver Mononuclear Phagocytes.
  • DOI:
    10.4049/jimmunol.1600306
  • 发表时间:
    2016-06-15
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Bettina A;Zhang Z;Michels K;Cagnina RE;Vincent IS;Burdick MD;Kadl A;Mehrad B
  • 通讯作者:
    Mehrad B
Prevalence of obstructive coronary artery disease in patients undergoing lung transplantation: case series and review of the literature.
接受肺移植的患者阻塞性冠状动脉疾病的患病率:病例系列和文献综述。
Dose-dependent Effect of Statin Therapy on Circulating CXCL12 Levels in Patients with Hyperlipidemia.
  • DOI:
    10.1186/2001-1326-1-23
  • 发表时间:
    2012-10-06
  • 期刊:
  • 影响因子:
    10.6
  • 作者:
    Camnitz W;Burdick MD;Strieter RM;Mehrad B;Keeley EC
  • 通讯作者:
    Keeley EC
Sporadic Obliterative Bronchiolitis: Case Series and Systematic Review of the Literature.
散发性闭塞性细支气管炎:病例系列和文献系统回顾。
Fibrocytes and the pathogenesis of diffuse parenchymal lung disease.
  • DOI:
    10.1186/1755-1536-5-s1-s22
  • 发表时间:
    2012
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Mehrad B;Strieter RM
  • 通讯作者:
    Strieter RM
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Borna Mehrad其他文献

Borna Mehrad的其他文献

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{{ truncateString('Borna Mehrad', 18)}}的其他基金

Neutrophils and adaptive immunity against invasive aspergillosis
中性粒细胞和针对侵袭性曲霉病的适应性免疫
  • 批准号:
    8996132
  • 财政年份:
    2015
  • 资助金额:
    $ 54.17万
  • 项目类别:
Fibrocytes in human pulmonary fibrosis
人肺纤维化中的纤维细胞
  • 批准号:
    8039366
  • 财政年份:
    2011
  • 资助金额:
    $ 54.17万
  • 项目类别:
Fibrocytes in human pulmonary fibrosis
人肺纤维化中的纤维细胞
  • 批准号:
    8231325
  • 财政年份:
    2011
  • 资助金额:
    $ 54.17万
  • 项目类别:
Fibrocytes in human pulmonary fibrosis
人肺纤维化中的纤维细胞
  • 批准号:
    8606488
  • 财政年份:
    2011
  • 资助金额:
    $ 54.17万
  • 项目类别:
Fibrocytes in human pulmonary fibrosis
人肺纤维化中的纤维细胞
  • 批准号:
    8427332
  • 财政年份:
    2011
  • 资助金额:
    $ 54.17万
  • 项目类别:
ROLE OF INFLAMMATION IN PULMONARY INJURY
炎症在肺损伤中的作用
  • 批准号:
    7415122
  • 财政年份:
    2004
  • 资助金额:
    $ 54.17万
  • 项目类别:
NK cells in host defense against invasive aspergillosis
NK 细胞在宿主防御侵袭性曲霉病中的作用
  • 批准号:
    7337024
  • 财政年份:
    2003
  • 资助金额:
    $ 54.17万
  • 项目类别:
NK cells in host defense against invasive aspergillosis
NK 细胞在宿主防御侵袭性曲霉病中的作用
  • 批准号:
    7654277
  • 财政年份:
    2003
  • 资助金额:
    $ 54.17万
  • 项目类别:
NK cells in host defense against invasive aspergillosis
NK 细胞在宿主防御侵袭性曲霉病中的作用
  • 批准号:
    7849622
  • 财政年份:
    2003
  • 资助金额:
    $ 54.17万
  • 项目类别:
NK cells in host defense against invasive aspergillosis
NK 细胞在宿主防御侵袭性曲霉病中的作用
  • 批准号:
    6942872
  • 财政年份:
    2003
  • 资助金额:
    $ 54.17万
  • 项目类别:

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