FLI1 in Pulmonary Arterial Hypertension

FLI1 在肺动脉高压中的作用

• 批准号: 10727278
• 负责人: Anna R Hemnes
• 金额: $ 17.5万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10727278
• 关键词: ABL1 gene; Adverse event; Affect; Animal Model; Automobile Driving; BMPR2 gene; Blood Vessels; Case Study; Cessation of life; Data; Development; Diagnosis; Disease; Endothelial Cells; Endothelium; Essential Hypertension; FDA approved; FLI1 gene; Fibroblast Growth Factor; Future; Goals; Grant; Growth Factor; Heritability; Human; Hypoxia; Imatinib; Impairment; Knock-out; Lesion; Lung; Modeling; Modernization; Mus; Mutation; Pathogenesis; Pathology; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Phase III Clinical Trials; Phenotype; Plasma; Platelet-Derived Growth Factor; Play; Proteins; Proteomics; Pulmonary arterial remodeling; Receptor Protein-Tyrosine Kinases; Rodent; Rodent Model; Role; Scleroderma; Skin; Small Interfering RNA; Stains; Testing; Transcriptional Activation; Translating; Tyrosine Kinase Inhibitor; Vascular Diseases; Work; arm; barrier to testing; bone; comparison control; endothelial dysfunction; exercise capacity; experimental study; improved; insight; mouse model; mutant; novel; novel therapeutics; overexpression; prevent; pulmonary arterial hypertension; pulmonary vascular disorder; pulmonary vascular remodeling; receptor; restoration; right ventricular failure; tool; transcription factor; young woman

Pulmonary arterial hypertension (PAH) is a rare and devastating disease resulting in pulmonary arterial remodeling, right heart failure and death. While there are FDA-approved therapies, none is curative. It has been recognized for years that growth factors, such as platelet-derived growth factor and fibroblast growth factor, act through tyrosine kinase receptors to promote pulmonary vascular remodeling in PAH. Imatinib, a non-specific tyrosine kinase inhibitor showed promise in animal models of PAH and several case reports demonstrated cures of PAH with imatinib. A Phase III clinical trial of imatinib in PAH showed marked improvement in exercise capacity in some patients but did not receive FDA approval because the drug was not well tolerated. We sought to understand novel mechanisms of imatinib effect in PAH. In preliminary data, we administered imatinib to mice that express a human mutation that is known to cause heritable forms of PAH (bone morphogenetic receptor type 2, BMPR2) and tested changes in plasma proteomics as a novel way of detecting key drug effects in a manner that could be translated to humans and may lend mechanistic insight. imatinib altered several proteins in the plasma with Friend leukemia virus integration 1 (Fli1) being the most significantly changed protein. Fli1 is a transcription factor whose function is increased after c-Abl engagement by imatinib. Interestingly, Fli1 deficiency is well described to play a role in the vasculopathy of the skin of patients with scleroderma, a condition closely associated with PAH. it is unknown if Fli1 deficiency plays a role in PAH however. We have used imatinib as a tool to understand mechanisms of pulmonary vascular dysfunction in PAH and uncovered that Fli1 may play a key role. Our overarching hypothesis is that Fli1 deficiency contributes to PAH development through disruption of endothelial barrier function and that restoration of Fli1 will restore endothelial function and improve PAH. We propose the following aims to test this hypothesis: Aim 1. Test the hypothesis endothelial barrier function is impaired in PAH and that increased Fli1 expression through imatinib exposure restores endothelial function in PAH. We will use cultured BMPR2 or control endothelial cells with and without imatinib and/or Fli1 siRNA to test barrier function and the role of Fli1 in regulating endothelial barrier function. Aim 2. Test the hypothesis that Fli1 deficiency is a rodent model of PAH, enhances pulmonary vascular disease in a rodent model of PAH and that Fli1 overexpression prevents rodent PAH. This aim will generate two mouse models: inducible global Fli1 knockout and inducible global overexpression of Fli1. We will determine these models exacerbate or improve an accepted rodent PAH model, Sugen+Hypoxia, and test for pulmonary vascular leak in these models. This proposal will generate necessary tools to study the role of FLI1 in PAH. In the long term, this work will develop novel, well-tolerated disease modifying therapies for this rare and highly morbid disease.

肺动脉高压（PAH）是一种罕见而毁灭性的疾病，导致肺动脉 重塑，正确的心力衰竭和死亡。尽管有FDA批准的疗法，但没有治愈性。它有 多年来，人们认识到生长因素，例如血小板衍生的生长因子和成纤维细胞生长 因素，通过酪氨酸激酶受体起作用，以促进PAH中的肺血管重塑。伊马替尼 非特异性酪氨酸激酶抑制剂在PAH动物模型和几个病例报告中显示出希望 用伊马替尼展示了PAH的治疗方法。伊马替尼在PAH中的III期临床试验显示出标记 某些患者的运动能力提高，但没有获得FDA批准，因为该药物不是 容忍良好。我们试图了解伊马替尼在PAH中的新型机制。在初步数据中，我们 对伊马替尼的施用到表达人类突变的小鼠，该突变已知会引起可遗传的pah （骨形态发生受体2型，BMPR2），并测试了血浆蛋白质组学的变化作为一种​​新颖的方式 以可以转化为人类的方式检测关键药物作用并可能提供机械洞察力。 伊马替尼用朋友白血病病毒整合1（fli1）改变了血浆中的几种蛋白质 显着改变了蛋白质。 FLI1是转录因子，其功能在C-ABL参与后会增加 由伊马替尼。有趣的是，FLI1缺乏症可以很好地描述在皮肤的脉管病中发挥作用 硬皮病患者，与PAH密切相关的疾病。未知FLI1缺乏症是否起作用 但是，在PAH中。我们已经使用伊马替尼作为了解肺血管机制的工具 PAH的功能障碍并发现FLI1可能起关键作用。我们的总体假设是FLI1 缺乏通过破坏内皮屏障功能而导致PAH的发展，并且 FLI1的恢复将恢复内皮功能并改善PAH。我们建议以下目标 检验以下假设：目标1。检验假设内皮屏障功能在PAH中受到损害 通过伊马替尼暴露增加FLI1表达可恢复PAH中的内皮功能。我们将使用 有或没有伊马替尼和/或FLI1 siRNA的培养的BMPR2或控制内皮细胞测试屏障功能 FLI1在调节内皮屏障功能中的作用。目标2。检验FLI1缺乏症的假设 是PAH的啮齿动物模型，在PAH的啮齿动物模型中增强了肺血管疾病 FLI1过表达可防止啮齿动物PAH。该目标将产生两个鼠标：诱导全局FLI1 FLI1的敲除和诱导的全球过表达。我们将确定这些模型加剧或改进 这些模型中接受的啮齿动物PAH模型，Sugen+缺氧和肺血管泄漏的测试。这 提案将生成必要的工具来研究FLI1在PAH中的作用。从长远来看，这项工作将发展 新型，耐受性良好的疾病修饰这种罕见且病态疾病的疗法。