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）是一种罕见且毁灭性的疾病，会导致肺动脉高压 重塑、右心衰竭和死亡。虽然有 FDA 批准的疗法，但没有一种是有效的。它有 多年来人们认识到生长因子，例如血小板源性生长因子和成纤维细胞生长 因子，通过酪氨酸激酶受体发挥作用，促进 PAH 中的肺血管重塑。伊马替尼，一种 非特异性酪氨酸激酶抑制剂在 PAH 动物模型和一些病例报告中显示出前景 证明伊马替尼可以治愈 PAH。伊马替尼治疗 PAH 的 III 期临床试验显示显着 改善了一些患者的运动能力，但没有获得 FDA 批准，因为该药物不适合 耐受性良好。我们试图了解伊马替尼治疗肺动脉高压的新机制。在初步数据中，我们 给表达人类突变的小鼠注射伊马替尼，这种突变已知会导致遗传性多环芳烃 （骨形态发生受体 2 型，BMPR2）并测试血浆蛋白质组学的变化作为一种​​新方法 以一种可以转化为人类的方式检测关键药物效应，并可能提供机制洞察力。 伊马替尼改变了血浆中的多种蛋白质，其中弗兰德白血病病毒整合 1 (Fli1) 变化最大 蛋白质发生显着改变。 Fli1 是一种转录因子，其功能在 c-Abl 参与后增强 通过伊马替尼。有趣的是，Fli1 缺陷被充分描述在皮肤血管病变中发挥作用。 患有硬皮病的患者，这是一种与 PAH 密切相关的疾病。目前尚不清楚 Fli1 缺陷是否起作用 然而在PAH中。我们使用伊马替尼作为了解肺血管机制的工具 PAH 功能障碍并发现 Fli1 可能发挥关键作用。我们的首要假设是 Fli1 缺乏通过破坏内皮屏障功能促进多环芳烃的发展 Fli1 的恢复将恢复内皮功能并改善 PAH。我们提出以下目标 检验该假设：目标 1. 检验 PAH 患者内皮屏障功能受损的假设，以及 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 使用或不使用伊马替尼和/或 Fli1 siRNA 培养 BMPR2 或对照内皮细胞以测试屏障功能 以及 Fli1 在调节内皮屏障功能中的作用。目标 2. 检验 Fli1 缺陷的假设 是 PAH 啮齿动物模型，增强 PAH 啮齿动物模型中的肺血管疾病，并且 Fli1 过度表达可预防啮齿动物 PAH。该目标将生成两个小鼠模型：诱导型全局 Fli1 Fli1 的敲除和诱导性全局过度表达。我们将确定这些模型加剧或改善 一种公认的啮齿动物 PAH 模型 Sugen+Hypoxia，并在这些模型中测试肺血管渗漏。这 该提案将产生必要的工具来研究 FLI1 在 PAH 中的作用。从长远来看，这项工作将得到发展 针对这种罕见且高度发病的疾病的新型、耐受性良好的疾病修饰疗法。