Molecular regulation of BMPRII stability in lung fibrosis

肺纤维化中 BMPRII 稳定性的分子调节

• 批准号: 10712273
• 负责人: Yutong Zhao
• 金额: $ 50.02万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712273
• 关键词: Ablation; Aging; Architecture; BMP4; BMPR2 gene; Back; Bone Morphogenetic Proteins; Cells; Chronic; Cicatrix; Data; Development; Docking; Down-Regulation; Epithelial Cells; Exhibits; Extracellular Matrix; Failure; Fibroblasts; Fibrosis; Genetic; Impairment; Injury; Knowledge; Link; Lipid Peroxidation; Lung; Lung diseases; Lysosomes; Mediating; Modeling; Molecular; Mus; Myofibroblast; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Play; Polyubiquitin; Polyubiquitination; Production; Property; Proteins; Pulmonary Fibrosis; Regulation; Resolution; Role; Scheme; Signal Induction; Signal Pathway; Signal Transduction; Signaling Protein; Site; System; Testing; Therapeutic; Transforming Growth Factors; Ubiquitination; Up-Regulation; bone morphogenetic protein receptors; cell injury; effective therapy; fibrotic lung; fibrotic lung disease; gain of function; healing; idiopathic pulmonary fibrosis; loss of function; lung development; novel; novel therapeutic intervention; overexpression; prevent; protein function; proteostasis; repaired; response; restoration; success; therapy development; ubiquitin-protein ligase

Abstract Idiopathic Pulmonary Fibrosis (IPF) is a chronic, irreversible, aging-associated, and ultimately fatal lung disease. The median survival of pulmonary fibrosis patients is only 4-5 years. There is no treatment to reverse fibrosis and cure IPF. Development of anti-fibrotic therapeutics is an unmet need in the treatment of IPF. The relentless progression of IPF is due in part to the failure of fibrosis resolution. The development of therapies for IPF relies on the comprehensive understanding of fibrosis resolution pathways. Accumulating evidence shows that activation of BMPs signaling induces myofibroblast de-differentiation and fibrosis resolution. A key receptor, BMP receptor II (BMPRII), in BMPs signaling has been shown to be reduced in fibrotic lungs; thus, restoration of BMPRII in fibrotic lungs is a potential therapy to treat IPF. However, molecular regulation of BMPRII stability has not been well studied. In our preliminary data, we discovered that (i) BMPRII is degraded in the lysosome system in response to TGF-β1 and lipid peroxidation inducers, which play critical roles in the development of lung fibrosis; (ii) Nedd4L stabilizes BMPRII; (iii) downregulation of Nedd4L reduced BMP4 signaling and the effects were rescued by overexpression of BMPRII; (iv) overexpression of Nedd4L promoted de-differentiation of lung myofibroblasts. Based on these novel observations, we hypothesized that Nedd4L promotes BMPRII stability and facilitates BMPs/BMPRII-mediated myofibroblast de-differentiation and pulmonary fibrosis resolution. We propose three Specific Aims to evaluate our hypothesis. First, we will determine the regulatory mechanisms by which Nedd4L stabilizes BMPRII. We will identify the ubiquitination and Nedd4L docking sites on BMPRII and determine the effect of Nedd4L-mediated K63-linked ubiquitination on BMPRII internalization and stability. Next, we will determine if Nedd4L suppression is essential for TGF-β1- and lipid peroxidation-induced BMPRII degradation. Finally, we will determine if Nedd4L facilitates lung fibrosis resolution through stabilization of BMPRII and promotion of BMPs-mediated myofibroblast de-differentiation and inactivation. We will determine if elevated BMPRII stability by Nedd4L facilitates myofibroblast de-differentiation in ex-vivo cultured lung myofibroblasts. An inducible fibroblast specific Nedd4L depletion mouse will be used in both resolving and non- resolving lung fibrosis models. The proposed studies will address key knowledge gaps regarding molecular regulation of BMPRII stability and anti-fibrotic effects of BMPs/BMPRII. Success of the proposed studies will suggest that targeting Nedd4L/BMPRII to rescue BMPRII expression in fibrotic lungs may lead to new opportunities to halt pro-fibrotic progression and promote fibrosis resolution.

抽象的 特发性肺纤维化（IPF）是一种慢性，不可逆的，与老化相关的，最终是致命的肺部疾病。 肺纤维化患者的中位存活率仅为4 - 5年。没有逆转纤维化的治疗方法 和治愈IPF。抗纤维化疗法的发展是IPF治疗中未满足的需求。友好 IPF的进展部分归因于纤维化分辨率的失败。 IPF疗法的开发依赖 关于纤维化分辨率途径的全面理解。积累的证据表明 BMPS信号传导的激活诱导肌纤维细胞去分化和纤维化分辨率。关键受体BMP 受体II（BMPRII），在BMPS信号中已显示在纤维化肺中降低。因此，恢复 纤维化肺中的BMPRII是治疗IPF的潜在疗法。但是，BMPRII稳定性的分子调节具有 研究不好。在我们的初步数据中，我们发现（i）BMPRII在溶酶体系统中降解 响应TGF-β1和脂质过氧化影响者，这些影响者在肺纤维化发展中起着关键作用。 （ii）NEDD4L稳定BMPRII； （iii）NEDD4L的下调降低了BMP4信号，效果为 通过BMPRII的过表达救助； （iv）NEDD4L的过表达促进了肺的脱不同 肌纤维细胞。基于这些新的观察结果，我们假设NEDD4L促进了BMPRII稳定性 并促进BMP/BMPRII介导的肌纤维细胞脱不同和肺纤维化分辨率。我们 提案三个特定的目的是评估我们的假设。首先，我们将通过 NEDD4L稳定BMPRII。我们将在BMPRII和 确定NEDD4L介导的K63连接泛素化对BMPRII内在化和稳定性的影响。下一个， 我们将确定NEDD4L抑制是否对于TGF-β1-和脂质过氧化诱导的BMPRII至关重要 降解。最后，我们将确定NEDD4L是否通过稳定来促进肺纤维化。 BMPRII和BMPS介导的肌纤维细胞去分化和失活的促进。我们将确定是否 NEDD4L升高BMPRII稳定性，促进了前体培养的肺中的肌纤维细胞脱不同 肌纤维细胞。可诱导的成纤维细胞特异性NEDD4L部署鼠标将用于分辨和非 - 解决肺纤维化模型。拟议的研究将解决有关分子的关键知识差距 BMPS/BMPRII的BMPRII稳定性和抗纤维化作用的调节。拟议研究的成功将 建议靶向NEDD4L/BMPRII营救纤维化肺中的BMPRII表达可能会导致新的 停止促纤维化进展并促进纤维化的机会。