Molecular and Cellular Pathogenesis of Pulmonary Langerhans Cell Histiocytosis

肺朗格汉斯细胞组织细胞增多症的分子和细胞发病机制

基本信息

  • 批准号:
    10658208
  • 负责人:
  • 金额:
    $ 56.78万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-05-01 至 2027-04-30
  • 项目状态:
    未结题

项目摘要

Project Summary. Pulmonary Langerhans Cell Histiocytosis (PLCH) is a rare interstitial lung disease, which occurs almost exclusively in cigarette smokers and has a median duration of survival from of of 12.5 years. PLCH is characterized by,Langerin+ dendritic cell (DC) accumulation, inflammatory lesions, nodule formation and cystic remodeling. Recently, a causative link between acquired BRAF (kinase in RAS pathway) mutations in the myeloid/monocyte lineage and the development of benign neoplasms has been reported, and a common, acquired mutation in BRAF (V600E) was found in lung lesions of more than half of PLCH patients. Although this causal link represents an important breakthrough, the mechanisms by which mutant histiocytes control the initiation and progression of PLCH are unknown. To address this critical knowledge gap, we have developed preclinical models that recapitulate hallmark features of PLCH. We show that cigarette smoke (CS) exposure of mice expressing an inducible BRAFV600E mutation in CD11c+ cells exhibit peribronchiolar inflammation, nodule formation, and airspace enlargement accompanied by cyst-like formations. These structural changes are accompanied by alterations in DC homeostasis, including increased expression of and responsiveness to the chemokine CCL20. Further, our data suggest the BRAFV600E-dependent production of the pleiotropic cytokine CCL7 is a potential driver of the inflammatory lesions in PLCH. Finally, we demonstrate that the BRAF mutation induces DC senescence accompanied by upregulation of non-classical MHC ligands that permit the DCs to evade immune-mediated clearance. Based on these novel preliminary data, we hypothesize that PLCH pathogenesis is initiated by a combination of BRAF mutations along with CS exposure to amplify CCL20 mediated histiocyte accumulation followed by the recruitment of inflammatory cells/nodule development via CCL7 production and the amplification of this process is preserved by BRAF-dependent expression of ligands for inhibitory receptors on cytotoxic lymphocytes. We will test this hypothesis with three inter-related, yet independent, Specific Aims. We expect the completion of the research will lead to new conceptual advances in PLCH. While PLCH is rare, we believe the preclinical model will lead to insights into the role of BRAFV600E cells in PLCH. This model provides a compelling platform for preclinical studies in the short term and evidence based clinical trials in the long term, and should enable the development of treatments of a life threatening pulmonary disease. This goal may be viewed as aggressive but the identification of an effective treatment for lymphanioleiomyomatosis by our group and promising clinical trials underway by our group as part of the Rare Lung Disease Consortium, are direct evidence that effective therapies can be found quickly when clues of nature are abundant, molecular targets are known, biological plausibility is high and patient communities are well organized.
项目摘要。肺朗格汉斯细胞组织细胞增生症(PLCH)是一种罕见的间质性肺部疾病, 它几乎只发生在吸烟者中,存活时间的中位数是 12.5年。PLCH的特点是,Langerin+树突状细胞(DC)聚集,炎性病变, 结节形成和囊性重塑。最近,获得性BRAF(蛋白激酶)之间的因果联系 髓系/单核细胞系RAS通路突变与良性肿瘤发生 已有报道,在肺脏病变中发现了一种常见的BRAF(V600E)获得性突变 超过一半的PLCH患者。尽管这种因果联系是一项重要的突破,但 突变的组织细胞控制PLCH的启动和进展的机制尚不清楚。至 为了解决这一关键的知识鸿沟,我们开发了概括标志的临床前模型 PLCH的特点。我们发现,香烟烟雾(CS)暴露的小鼠表达了一种可诱导的 CD11c+细胞中的BRAFV600E突变表现为细支气管炎、结节形成和 空域扩大并伴有囊状结构。这些结构性变化是伴随着 通过DC动态平衡的改变,包括增加表达和对 趋化因子CCL20。此外,我们的数据表明,BRAFV600E依赖于多效性的生产 细胞因子CCL7是PLCH炎性损害的潜在驱动因素。最后,我们证明了 BRAF突变诱导DC衰老伴随非经典MHC配体上调 允许DC逃避免疫调节的清除。基于这些新颖的初步数据,我们 假设PLCH的发病机制是由BRAF突变和CS的组合启动的 暴露于放大CCL20介导的组织细胞聚集后,炎性细胞的招募 通过产生CCL7来发育细胞/结节,这一过程的放大通过 细胞毒性淋巴细胞上抑制受体配体的BRAF依赖性表达。我们将对此进行测试 有三个相互关联但又相互独立的特定目标的假设。我们预计可完成 研究将导致PLCH在概念上的新进展。虽然PLCH很少见,但我们认为临床前 模型将导致对BRAFV600E细胞在PLCH中的作用的深入了解。该模型提供了一个引人注目的 短期临床前研究和长期循证临床试验平台,以及 应该能够开发出一种威胁生命的肺部疾病的治疗方法。这个目标可能是 被认为是侵袭性的,但我们的研究发现了一种治疗淋巴管肌瘤病的有效方法 作为罕见肺部疾病联盟的一部分,我们小组正在进行有希望的临床试验, 直接证据表明,当自然界的线索丰富时,有效的治疗方法可以很快找到, 分子靶标是已知的,生物学上的可信度很高,患者社区组织得很好。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Michael Borchers其他文献

Michael Borchers的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Michael Borchers', 18)}}的其他基金

Natural Killer Cell Subpopulations in COPD Exacerbations
COPD 恶化中的自然杀伤细胞亚群
  • 批准号:
    10316151
  • 财政年份:
    2020
  • 资助金额:
    $ 56.78万
  • 项目类别:
Natural Killer Cell Subpopulations in COPD Exacerbations
COPD 恶化中的自然杀伤细胞亚群
  • 批准号:
    10578653
  • 财政年份:
    2020
  • 资助金额:
    $ 56.78万
  • 项目类别:
Natural Killer Cell Subpopulations in COPD Exacerbations
COPD 恶化中的自然杀伤细胞亚群
  • 批准号:
    10012049
  • 财政年份:
    2020
  • 资助金额:
    $ 56.78万
  • 项目类别:
Natural Killer Cell Functions in Lymphangioleiomyomatosis
自然杀伤细胞在淋巴管平滑肌瘤病中的功能
  • 批准号:
    10323021
  • 财政年份:
    2019
  • 资助金额:
    $ 56.78万
  • 项目类别:
Clec5a regulation of Macrophage function in COPD
Clec5a 对 COPD 巨噬细胞功能的调节
  • 批准号:
    8696486
  • 财政年份:
    2014
  • 资助金额:
    $ 56.78万
  • 项目类别:
Clec5a regulation of Macrophage function in COPD
Clec5a 对 COPD 巨噬细胞功能的调节
  • 批准号:
    9040253
  • 财政年份:
    2014
  • 资助金额:
    $ 56.78万
  • 项目类别:
Clec5a regulation of Macrophage function in COPD
Clec5a 对 COPD 巨噬细胞功能的调节
  • 批准号:
    9247243
  • 财政年份:
    2014
  • 资助金额:
    $ 56.78万
  • 项目类别:
Novel Reagents in Mouse Models of Autoimmune COPD
自身免疫性慢性阻塞性肺病小鼠模型中的新型试剂
  • 批准号:
    8166497
  • 财政年份:
    2011
  • 资助金额:
    $ 56.78万
  • 项目类别:
Novel Reagents in Mouse Models of Autoimmune COPD
自身免疫性慢性阻塞性肺病小鼠模型中的新型试剂
  • 批准号:
    8313878
  • 财政年份:
    2011
  • 资助金额:
    $ 56.78万
  • 项目类别:
Shared Mechanisms of Pulmonary Lymphocyte Activation by Bacteria and Toxicants
细菌和毒物激活肺淋巴细胞的共同机制
  • 批准号:
    7163144
  • 财政年份:
    2006
  • 资助金额:
    $ 56.78万
  • 项目类别:

相似海外基金

Time to ATTAC: Adoptive Transfer of T cells Against gp100+ Cells to treat LAM
ATTAC 时间:针对 gp100 细胞的 T 细胞过继转移来治疗 LAM
  • 批准号:
    10682121
  • 财政年份:
    2023
  • 资助金额:
    $ 56.78万
  • 项目类别:
Phase I clinical trial of adoptive transfer of autologous folate receptor-alpha redirected CAR T cells for ovarian cancer
自体叶酸受体-α重定向CAR T细胞过继转移治疗卵巢癌的I期临床试验
  • 批准号:
    10576370
  • 财政年份:
    2022
  • 资助金额:
    $ 56.78万
  • 项目类别:
Phase I clinical trial of adoptive transfer of autologous folate receptor-alpha redirected CAR T cells for ovarian cancer
自体叶酸受体-α重定向CAR T细胞过继转移治疗卵巢癌的I期临床试验
  • 批准号:
    10387023
  • 财政年份:
    2022
  • 资助金额:
    $ 56.78万
  • 项目类别:
Determining mechanisms of enhanced antitumor efficacy of four-day expanded Th17 cells for adoptive transfer
确定用于过继转移的四天扩增 Th17 细胞增强抗肿瘤功效的机制
  • 批准号:
    10248409
  • 财政年份:
    2019
  • 资助金额:
    $ 56.78万
  • 项目类别:
A phase I clinical study of adoptive transfer of regulatory T cells (Tregs) and low-dose interleukin-2 (IL-2) for the treatment of chronic graft-versus-host disease (GVHD): gene-marking to inform rational combination therapy
调节性 T 细胞 (Treg) 和低剂量白细胞介素 2 (IL-2) 过继转移治疗慢性移植物抗宿主病 (GVHD) 的 I 期临床研究:基因标记为合理的联合治疗提供信息
  • 批准号:
    nhmrc : GNT1163111
  • 财政年份:
    2019
  • 资助金额:
    $ 56.78万
  • 项目类别:
    Project Grants
Determining mechanisms of enhanced antitumor efficacy of four-day expanded Th17 cells for adoptive transfer
确定用于过继转移的四天扩增 Th17 细胞增强抗肿瘤功效的机制
  • 批准号:
    10462684
  • 财政年份:
    2019
  • 资助金额:
    $ 56.78万
  • 项目类别:
Gene edited lymphoid progenitors for adoptive transfer as a treatment of primary immunodeficiency
基因编辑的淋巴祖细胞用于过继转移作为原发性免疫缺陷的治疗
  • 批准号:
    398018062
  • 财政年份:
    2018
  • 资助金额:
    $ 56.78万
  • 项目类别:
    Research Grants
Overcoming immune suppression in cancer by targeting PSGL-1 in T cells used for adoptive transfer
通过靶向用于过继转移的 T 细胞中的 PSGL-1 克服癌症中的免疫抑制
  • 批准号:
    9308643
  • 财政年份:
    2017
  • 资助金额:
    $ 56.78万
  • 项目类别:
Overcoming immune suppression in cancer by targeting PSGL-1 in T cells used for adoptive transfer
通过靶向用于过继转移的 T 细胞中的 PSGL-1 克服癌症中的免疫抑制
  • 批准号:
    9447149
  • 财政年份:
    2017
  • 资助金额:
    $ 56.78万
  • 项目类别:
Targeting Cancer miRNAs by Adoptive Transfer of Programmed B Lymphocytes
通过程序化 B 淋巴细胞的过继转移靶向癌症 miRNA
  • 批准号:
    8893915
  • 财政年份:
    2014
  • 资助金额:
    $ 56.78万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了