avb6-mediated TGFb activation in radiation lung fibrosis

avb6介导的放射性肺纤维化中的TGFb激活

• 批准号: 7258893
• 负责人: John S Munger
• 金额: $ 40.06万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-05 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7258893
• 关键词: Affect; Aftercare; Animal Model; Antibodies; Applications Grants; Biological; Biological Availability; Bleomycin; C57BL/6 Mouse; Chest; Complement; Complex; Control Animal; Development; Disease; Dose; Dose-Limiting; Epithelial Cells; Epithelium; Event; Evolution; Exposure to; Extracellular Matrix; Feedback; Fibrosis; Gene Dosage; Genes; Genetic; Genetic Transcription; Goals; Human; Immobilization; Individual; Inflammation; Integrin Binding; Integrins; Knock-in Mouse; Knockout Mice; Lead; Ligands; Ligation; Lung; Measures; Mediating; Mus; Mutation; Normal tissue morphology; Organ; Oxidants; Pathogenesis; Patients; Peptides; Phenotype; Plasma; Prevention; Process; Pulmonary Fibrosis; Radiation; Radiation Pneumonitis; Radiation therapy; Reagent; Resistance; Risk; Role; Signal Transduction; System; Systemic Therapy; Testing; Toxic effect; Transforming Growth Factor beta; Up-Regulation; Wild Type Mouse; Work; cytokine; extracellular; inhibitor/antagonist; integrin alphavbeta6; irradiation; mutant; prevent; radiation effect; receptor function; research study; response; treatment effect; tumor

DESCRIPTION (provided by applicant): Radiation-induced pulmonary fibrosis (RIPF) is one of the major dose-limiting toxicities of thoracic radiation. It is generally believed that the fibrogenic cytokine TGFbeta1 is necessary for the development of RIPF, although this hypothesis has not been directly tested in animal models. Because TGFbeta1 is secreted in a latent form, TGFbeta1 activity is controlled by an activation step. TGFbeta1 latency is due to interaction of TGFbeta1 with its propeptide, Latency-Associated Peptide (LAP). TGFbeta1 signaling occurs following release of TGFbeta1 from LAP. We discovered that LAP is a ligand for an epithelium-specific integrin, alphavbeta6. Following ligation of LAP by alphavbeta6, TGFbeta1 is released. Therefore, by expressing alphavbeta6, epithelial cells locally activate TGFbeta1. Mice lacking alphavbeta6 (beta6-/- mice) do not develop lung fibrosis after exposure to bleomycin. Recently, we generated mice with a knocked-in mutation in TGFbeta1-LAP that abrogates integrin binding (TGFbeta1-RGE mice). The phenotype of these mice reproduces that of TGFbeta1-/- mice, indicating that integrin-mediated TGFbeta1 activation is a major (and perhaps the only) mechanism for generating active TGFbeta1. We have also found that beta6-/- mice do not develop RIPF. Furthermore, wild type mice sharply upregulate alphavbeta6 expression in lung epithelium as a late event after thoracic irradiation, just prior to the onset of RIPF. These results suggest that alphavbeta6-mediated TGFbeta1 activation is required for RIPF, and suggest 2 treatment strategies: inhibition of alphavbeta6 function, and prevention of alphavbeta6 upregulation. Our overall goal is to treat and/or prevent RIPF by inhibiting the alphavbeta6-TGFbeta1 activation system. We propose 3 aims. First, we will confirm that TGFbeta1 is required for RIPF. This will be done by treating irradiated mice with a TGFbeta antagonist and also by measuring the fibrotic response of TGFbeta1+/- mice. Second, we will test whether an alphavbeta6 inhibitor (a murine anti-alphavbeta6 mAb) reverses and/or prevents RIPF. If this reagent works, it should be considered as a potential therapy in human RIPF, and perhaps in radiation fibrosis affecting other organs. Measuring the fibrotic response of TGFbeta1-RGE+/- mice will also test the role of integrin-mediated TGFbeta1 activation in RIPF. Third, we will test the hypothesis that alphavbeta6 upregulation in lung epithelium, which occurs just prior to the development of RIPF, is due to increased TGFbeta1 signaling.

描述（由申请方提供）：放射性肺纤维化（RIPF）是胸部放射的主要剂量限制性毒性之一。 通常认为，纤维化细胞因子TGF β 1是RIPF发展所必需的，尽管这一假设尚未在动物模型中直接验证。 由于TGF β 1是以潜伏形式分泌的，因此TGF β 1活性受活化步骤控制。 TGF β 1潜伏期是由于TGF β 1与其前肽潜伏相关肽（LTP）的相互作用。 TGF β 1信号传导发生在TGF β 1从胎盘释放之后。 我们发现LAP是上皮特异性整合素alphavbeta 6的配体。 在α v β 6连接TGF β 1后，TGF β 1被释放。 因此，通过表达α v β 6，上皮细胞局部激活TGF β 1。 缺乏α v β 6的小鼠（β 6-/-小鼠）在暴露于博来霉素后不会发生肺纤维化。 最近，我们产生了小鼠与敲入突变的TGF β 1-β 1，废除整合素结合（TGF β 1-RGE小鼠）。 这些小鼠的表型再现了TGF β 1-/-小鼠的表型，表明整合素介导的TGF β 1活化是产生活性TGF β 1的主要（也许是唯一）机制。 我们还发现，β 6-/-小鼠不会发生RIPF。 此外，野生型小鼠急剧上调alphavbeta 6在肺上皮细胞的表达，作为胸部照射后的晚期事件，就在RIPF发作之前。 这些结果表明，α v β 6介导的TGF β 1活化是RIPF所必需的，并提出了2种治疗策略：抑制α v β 6功能和预防α v β 6上调。 我们的总体目标是通过抑制α v β 6-TGF β 1激活系统来治疗和/或预防RIPF。 我们提出三个目标。 首先，我们将确认TGF β 1是RIPF所必需的。 这将通过用TGF β拮抗剂治疗辐射小鼠以及通过测量TGF β 1 +/-小鼠的纤维化反应来完成。 第二，我们将测试alphavbeta 6抑制剂（鼠抗alphavbeta 6 mAb）是否逆转和/或预防RIPF。 如果这种试剂起作用，它应该被认为是一种潜在的治疗人类RIPF的方法，也许在辐射纤维化影响其他器官。 测量TGF β 1-RGE+/-小鼠的纤维化反应也将测试整合素介导的TGF β 1活化在RIPF中的作用。 第三，我们将检验这一假设，即肺上皮细胞中α v β 6的上调，发生在RIPF发生之前，是由于TGF β 1信号的增加。