DUSP1 as a therapeutic target in fibroproliferative acute lung injury

DUSP1作为纤维增殖性急性肺损伤的治疗靶点

• 批准号: 9066180
• 负责人: David W. Riches
• 金额: $ 39.63万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9066180
• 关键词: Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Apoptotic; Biological Response Modifier Therapy; Bleomycin; Cicatrix; Clinical Trials; DUSP1 gene; Development; Disease; Evaluation; Exhibits; Fibrosis; Future; Genetic; Goals; Growth; Health; Human; Hydrochloric Acid; Individual; Inflammatory; Insulin-Like Growth Factor I; Knowledge; Lead; Light; Liquid substance; Lung; Lung Inflammation; Lung diseases; MAPK14 gene; MAPK8 gene; Mechanical ventilation; Mediating; Modeling; Morbidity - disease rate; Mus; Patients; Phenocopy; Phosphoric Monoester Hydrolases; Production; Protein Tyrosine Phosphatase; Protein phosphatase; Proteins; Publishing; Pulmonary Fibrosis; Respiratory physiology; Risk; Role; Secondary to; Signal Transduction; Specificity; Survivors; Testing; Therapeutic; Threonine; Time; Translating; Tyrosine; Wild Type Mouse; Work; base; cytokine; experience; genetic approach; genetic manipulation; human subject; improved; inhibitor/antagonist; insight; lung injury; macrophage; mitogen-activated protein kinase p38; mortality; mouse model; novel; novel therapeutic intervention; preclinical study; prevent; programs; repaired; response; small molecule; small molecule inhibitor; therapeutic target

DESCRIPTION (provided by applicant): Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are serious conditions with an unacceptably high overall mortality rate of ~25%. In addition, some patients develop a debilitating, persistent and sometimes fatal, fibrotic lung disease called fibroproliferative ALI. Unfortunately, there are no effective therapeutic approaches to prevent or treat this disorder. This project seeks to address this therapeutic need by investigating the role of dual specificity protein phosphatase-1 (DUSP1, aka MKP-1), a protein threonine/tyrosine phosphatase that dephosphorylates and inactivates the mitogen-activated protein kinases, p38 and JNK. In preliminary studies using mouse models of acute lung injury and fibrosis, we have shown that the development of lung fibrosis is ablated in mice lacking DUSP1. Our preliminary studies also show that genetic DUSP1 deficiency in mice impairs the ability of macrophages to undergo "alternative" programming leading to impaired production of pro-fibrotic growth factors including TGF-¿. These and other considerations have led us to hypothesize that DUSP1 is a therapeutic target that, when blocked, will reduce or prevent alternative macrophage programming, pro-fibrotic growth factor production and the development of ALI/ARDS-associated parenchymal lung fibrosis. These hypotheses will be addressed with three specific aims. Using genetic and conditional manipulation of DUSP1 expression in mouse models, the goal of Specific Aim 1 is to address the hypothesis that DUSP1 expression by macrophages is required for the development of fibroproliferative ALI. In Specific Aim 2, we will test the hypothesis that DUSP1-dependent fibrotic lung disease is mediated by alternatively programmed macrophages producing pro-fibrotic growth factors. Lastly, in Specific Aim 3, we will begin translating this work into humans by conducting pre-clinical studies in which we will assess two currently available small molecule DUSP1 expression inhibitors, currently approved for use in humans, for their ability to phenocopy DUSP1 deficiency and inhibit the development of parenchymal lung fibrosis in mice. Our proposed studies represent the first time that protein phosphatases have been investigated as therapeutic targets for the treatment of fibroproliferative ALI. Thus, a long-term goal of this proposal is to translate our anticipated findings into a clinical trial of DUSP1 inhibitors in ALI nd ARDS patients who are at risk for developing fibrotic lung disease. In addition, DUSP1 may also be a valid therapeutic target in other fibrotic lung disease, e.g. progressive pulmonary fibrosis.

描述（由申请人提供）：急性肺损伤（ALI）及其更严重的形式急性呼吸窘迫综合征（ARDS）是严重的疾病，总死亡率高达约25%。此外，一些患者会出现一种使人衰弱、持续甚至致命的纤维化肺病，称为纤维增生性ALI。不幸的是，没有有效的治疗方法来预防或治疗这种疾病。该项目旨在通过研究双特异性蛋白磷酸酶-1（DUSP 1，又名MKP-1）的作用来解决这种治疗需求，DUSP 1是一种蛋白质苏氨酸/酪氨酸磷酸酶，可使促分裂原活化蛋白激酶p38和JNK去磷酸化和失活。在使用急性肺损伤和纤维化小鼠模型的初步研究中，我们已经表明，在缺乏DUSP 1的小鼠中，肺纤维化的发展被消融。我们的初步研究还表明，小鼠的遗传DUSP 1缺陷会损害巨噬细胞进行“替代”编程的能力，导致包括TGF-β在内的促纤维化生长因子的产生受损。这些和其他考虑使我们假设DUSP 1是一个治疗靶点，当被阻断时，将减少或阻止替代的巨噬细胞编程，促纤维化生长因子的产生和ALI/ARDS相关的实质性肺纤维化的发展。这些假设将与三个具体目标进行讨论。在小鼠模型中使用DUSP 1表达的遗传和条件操作，特定目标1的目标是解决巨噬细胞表达DUSP 1是纤维增生性ALI发展所需的假设。在具体目标2中，我们将检验DUSP 1依赖性纤维化肺病由产生促纤维化生长因子的交替编程巨噬细胞介导的假设。最后，在具体目标3中，我们将开始将这项工作转化为人类 通过进行临床前研究，我们将评估目前批准用于人类的两种目前可用的小分子DUSP 1表达抑制剂在小鼠中复制DUSP 1缺陷和抑制实质肺纤维化发展的能力。我们提出的研究代表了蛋白磷酸酶首次被研究作为治疗纤维增生性ALI的治疗靶点。因此，该提案的长期目标是将我们预期的发现转化为DUSP 1抑制剂在有发生纤维化肺病风险的ALI和ARDS患者中的临床试验。此外，DUSP 1也可能是其他纤维化肺病（例如进行性肺纤维化）的有效治疗靶点。