Tyrosine kinase inhibition in pulmonary hypertension: experimental and clinical studies

酪氨酸激酶抑制治疗肺动脉高压：实验和临床研究

• 批准号: 162369895
• 负责人: Professor Dr. Hossein Ardeschir Ghofrani
• 金额: --
• 依托单位: Biomedizinisches Forschungszentrum Seltersberg (BFS)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/162369895?language=en
• 关键词: Tyrosine; kinase; inhibition; pulmonary; hypertension

The project aims to investigate the role of tyrosine kinases (TK) in the pathobiology of pulmonary vascular diseases. In this project we will investigate the role of different tyrosine kinases in experimental and clinical pulmonary hypertension. Experimentally, we will employ established models for pulmonary hypertension (PH). Elaborate screening tools like laser assisted microdissection of vascular compartments followed by quantitative RT-PCR will be employed to gain more insight in expression pattern of RTKs in plexiform lesions, neointima, media and adventitia. Interventional experiments will show, whether tyrosine kinase inhibitors with different inhibitory profiles can reverse pulmonary vascular remodeling. In addition, transgenic mouse models, like PDGF receptor (PDGFR)-beta overexpressing mice or discoidin domain receptor (DDR) knockout mice, will be employed to pinpoint the role of different tyrosine kinases and dependent pathways in PH. Along the same line, we will investigate the expression of RTK and the downstream signaling cascades in human lung tissue from patients with PAH. The overall goal is to alleviate abnormal proliferation of (peri-)vascular cells by means of tyrosine kinase inhibition and to achieve reversal of the structural remodeling in the diseased lung vasculature by interference with tyrosine kinase dependent signaling („Reverse Remodeling“).

该项目旨在研究酪氨酸激酶(TK)在肺血管疾病病理生物学中的作用。在这个项目中，我们将研究不同的酪氨酸激酶在实验性和临床肺动脉高压中的作用。在实验上，我们将采用已建立的肺动脉高压(PH)模型。我们将使用激光辅助显微解剖血管间隔和定量RT-PCR等复杂的筛选工具，以更深入地了解RTK在丛状病变、新生内膜、中膜和外膜中的表达模式。干预性实验将证明，不同抑制谱的酪氨酸激酶抑制剂是否可以逆转肺血管重构。此外，转基因小鼠模型，如PDGF受体(PDGFR)-β过表达小鼠或盘状结构域受体(DDR)敲除小鼠，将被用来确定不同的酪氨酸激酶和依赖通路在PH中的作用。沿着同样的思路，我们将研究RTK及其下游信号通路在PAH患者肺组织中的表达。总的目标是通过抑制酪氨酸激酶来缓解(周围)血管细胞的异常增殖，并通过干扰酪氨酸激酶依赖的信号转导(“反向重塑”)来逆转病变肺血管的结构重塑。