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、与衰老相关且最终致命的肺部疾病。 肺纤维化患者的中位生存期仅为4-5年，目前尚无逆转纤维化的治疗方法。 开发抗纤维化疗法是 IPF 治疗中尚未满足的需求。 IPF 的进展部分是由于纤维化消退失败造成的。IPF 疗法的开发依赖于此。 越来越多的证据表明，对纤维化消退途径的全面了解。 BMP 信号传导的激活可诱导肌成纤维细胞去分化和纤维化消退，这是一个关键受体 BMP。 已证明 BMP 信号传导中的受体 II (BMPRII) 在纤维化肺部中减少； 纤维化肺中的 BMPRII 是治疗 IPF 的潜在疗法，然而，BMPRII 稳定性的分子调节已成为可能。 在我们的初步数据中，我们发现 (i) BMPRII 在溶酶体系统中被降解。 响应 TGF-β1 和脂质过氧化诱导剂，它们在肺纤维化的发展中发挥着关键作用； (ii) Nedd4L 稳定 BMPRII；(iii) Nedd4L 的下调减少了 BMP4 信号传导，其效果为 BMPRII 的过度表达可挽救；(iv) Nedd4L 的过度表达促进肺去分化 基于这些新的观察，我们发现 Nedd4L 可以促进 BMPRII 的稳定性。 并促进 BMP/BMPRII 介导的肌成纤维细胞去分化和肺纤维化消退。 提出三个具体目标来评估我们的假设首先，我们将通过以下方式确定监管机制。 Nedd4L 可以稳定 BMPRII，我们将鉴定 BMPRII 上的泛素化和 Nedd4L 对接位点。 确定 Nedd4L 介导的 K63 连接泛素化对 BMPRII 内化和稳定性的影响。 我们将确定 Nedd4L 抑制对于 TGF-β1 和脂质过氧化诱导的 BMPRII 是否至关重要 最后，我们将确定 Nedd4L 是否通过稳定化来促进肺纤维化的消退。 BMPRII 和促进 BMP 介导的肌成纤维细胞去分化和失活我们将确定是否。 Nedd4L 提高 BMPRII 稳定性促进离体培养肺中肌成纤维细胞去分化 诱导性成纤维细胞特异性 Nedd4L 耗竭小鼠将用于解决和非肌成纤维细胞。 解决肺纤维化模型的问题所提出的研究将解决有关分子的关键知识差距。 BMPRII 稳定性的调节和 BMP/BMPRII 的抗纤维化作用将取得成功。 表明靶向 Nedd4L/BMPRII 来挽救纤维化肺中的 BMPRII 表达可能会导致新的结果 阻止促纤维化进展并促进纤维化消退的机会。