PKD Family Kinase Function and Signaling in Lung Fibroblasts

肺成纤维细胞中 PKD 家族激酶的功能和信号转导

• 批准号: 8048817
• 负责人: HUA TANG
• 金额: $ 20.13万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048817
• 关键词: Affect; Agonist; Anti-Inflammatory Agents; Architecture; Biology; Cells; Chronic; Collagen; Deposition; Disease Progression; Effector Cell; Etiology; Extracellular Matrix; Family; Fibroblasts; Fibronectins; Growth Factor; Growth Factor Receptors; Hamman-Rich syndrome; Human; Lead; Lesion; Lung; Lung diseases; Messenger RNA; Molecular; PDGFRB gene; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Platelet-Derived Growth Factor Receptor; Play; Procollagen; Production; Protein Isoforms; Proteins; Rest; Role; Serine; Severities; Signal Transduction; Survival Rate; Testing; Therapeutic Intervention; Threonine; Time; base; design; effective therapy; novel; protein kinase D; receptor expression; transcription factor

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and usually fatal lung disease of unknown etiology, characterized by lung fibroblast activation and proliferation, excessive deposition of extracellular matrix (ECM), and destruction of the normal lung architecture. Long-term survival of IPF patients is poor, with a 5-year survival rate of only 20%. Historically, anti-inflammatory agents have been the mainstay of therapy, but have been proven to be ineffective in reducing either the severity or progression of the disease. Hence, there is a profound need for the identification of novel drugable targets to develop efficacious new therapies for treating IPF patients. Because lung fibroblasts are primary effector cells in IPF, the identification of novel drugable molecules or pathways that control IPF lung fibroblast biology may lead to more specific and efficacious therapeutic intervention in IPF. In this proposal, we seek to determine whether the serine/threonine protein kinase D (PKD) family kinases play critical roles in IPF fibroblast activation, production of ECM, and expression of profibrotic growth factor receptors. PKD family kinases include PKD1, PKD2 and PKD3. Herein, we found for the first time that all the PKD isoforms were readily detected in fibroblastic foci, the hallmark lesions of IPF. We further showed that PKD1 and PKD2 were constitutively activated in primary IPF fibroblasts but not in control normal human lung fibroblasts. Moreover, PKD1 and PKD2 could be further activated by profibrotic growth factors in primary IPF fibroblasts. Interestingly, PKD inhibition markedly downregulated the protein levels of procollagen and fibronectin without significantly affecting their mRNA levels in IPF fibroblasts. Whereas, PKD inhibition markedly suppressed both mRNA and protein levels of profibrotic platelet-derived growth factor receptor-( (PDGFR() in the fibroblasts. On the basis of these novel findings, this resubmission R21 proposal is designed to test the hypothesis that PKD family kinases may play critical roles in IPF fibroblast biology, including the fibroblast activation, ECM production and expression of profibrotic growth factor receptors, which may offer novel drugable targets for halting IPF progression. The Specific Aims of this resubmission proposal are: Aim 1) To characterize the constitutive and profibrotic agonist-induced activation of PKD family kinases in primary IPF fibroblasts; Aim 2) To determine the roles of PKD family kinases and the mechanisms in the production of profibrotic matrix in primary IPF fibroblasts; Aim 3) To determine the roles of PKD family kinases and the mechanisms in IPF fibroblast expression of profibrotic PDGF receptor-(. We anticipate that this proposal will identify PKD family kinases as novel and important modulators of lung fibroblast biology involved in the pathogenesis and progression of IPF, therefore targeting to inhibit PKD family kinases or a specific PKD isoform may provide a novel and efficacious therapeutic intervention for IPF patients. PUBLIC HEALTH RELEVANCE: This resubmission R21 proposal is designed to test the hypothesis that PKD family kinases may play critical roles in lung fibroblast biology, including the fibroblast activation, production of extracellular matrix, and expression of profibrotic growth factor receptors, which may offer novel drugable targets for halting the progression of idiopathic pulmonary fibrosis.

描述（由申请人提供）：特发性肺纤维化（IPF）是一种病因不明的慢性、进行性且通常致命的肺部疾病，其特征是肺成纤维细胞活化和增殖、细胞外基质（ECM）过度沉积以及正常肺的破坏建筑学。 IPF患者的长期生存率较差，5年生存率仅为20%。从历史上看，抗炎药一直是治疗的主要手段，但已被证明不能有效减轻疾病的严重程度或进展。因此，迫切需要鉴定新的药物靶点，以开发治疗 IPF 患者的有效新疗法。由于肺成纤维细胞是 IPF 中的主要效应细胞，因此识别控制 IPF 肺成纤维细胞生物学的新型药物分子或途径可能会导致对 IPF 进行更特异和有效的治疗干预。在本提案中，我们试图确定丝氨酸/苏氨酸蛋白激酶 D (PKD) 家族激酶是否在 IPF 成纤维细胞激活、ECM 产生和促纤维化生长因子受体表达中发挥关键作用。 PKD 家族激酶包括 PKD1、PKD2 和 PKD3。在此，我们首次发现所有 PKD 亚型均可在成纤维细胞病灶（IPF 的标志性病变）中轻易检测到。我们进一步表明 PKD1 和 PKD2 在原代 IPF 成纤维细胞中被组成性激活，但在对照正常人肺成纤维细胞中则没有。此外，原代IPF成纤维细胞中的促纤维化生长因子可以进一步激活PKD1和PKD2。有趣的是，PKD 抑制显着下调 IPF 成纤维细胞中原胶原和纤连蛋白的蛋白质水平，而没有显着影响它们的 mRNA 水平。然而，PKD 抑制显着抑制成纤维细胞中促纤维化血小板衍生生长因子受体 (PDGFR()) 的 mRNA 和蛋白质水平。基于这些新发现，此重新提交 R21 提案旨在检验 PKD 家族的假设激酶可能在 IPF 成纤维细胞生物学中发挥关键作用，包括成纤维细胞激活、ECM 产生和促纤维化生长因子受体表达，这可能为阻止 IPF 进展提供新的药物靶点。该重新提交提案的具体目标是： 目标 1) 表征原代 IPF 成纤维细胞中 PKD 家族激酶的组成型和促纤维化激动剂诱导的激活；目标 2) 确定 PKD 家族激酶的作用以及促纤维化产生的机制。原代 IPF 成纤维细胞中的基质；目标 3) 确定 PKD 家族激酶的作用以及 IPF 成纤维细胞表达促纤维化 PDGF 受体的机制。我们预计该提案将确定 PKD 家族激酶作为参与发病机制和进展的肺成纤维细胞生物学的新型重要调节剂因此，靶向抑制 PKD 家族激酶或特定的 PKD 亚型可能为 IPF 患者提供新颖且有效的治疗干预措施。 公共健康相关性：此重新提交 R21 提案旨在检验 PKD 家族激酶可能在肺成纤维细胞生物学中发挥关键作用的假设，包括成纤维细胞活化、细胞外基质的产生和促纤维化生长因子受体的表达，这可能提供新的药物阻止特发性肺纤维化进展的目标。