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

基本信息

批准号：
8503966
负责人：
David W. Riches
金额：
$ 37.72万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8503966
关键词：
Acute 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 Factor 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 manipulation human subject improved inhibitor/antagonist insight lung development lung injury macrophage mitogen-activated protein kinase p38 mortality mouse model novel novel therapeutic intervention preclinical study prevent programs public health relevance repaired response small molecule therapeutic target

项目摘要

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（由适用提供）：急性肺损伤（ALI）及其更严重的形式，急性呼吸窘迫综合征（ARDS）是严重的条件，总体死亡率高约25％。此外，一些患者会出现一种使人衰弱，持久性，有时是致命的纤维化肺部疾病，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。该项目试图通过研究双重特异性蛋白磷酸酶-1（DUSP1，又名MKP-1）的作用来解决该理论的需求，这是一种蛋白质苏氨酸/酪氨酸磷酸酶，从而降低并失活了有丝裂料激活的蛋白激酶，P38和JNK。在使用急性肺损伤和纤维化的小鼠模型的初步研究中，我们表明肺纤维化的发展是在缺乏DUSP1的小鼠中消化的。我们的初步研究还表明，小鼠的遗传DUSP1缺乏症会损害巨噬细胞进行“替代”编程的能力，从而导致促纤维化生长因子的产生受损，包括TGF- - 。这些和其他考虑因素使我们假设DUSP1是一个治疗靶标，在阻塞时，它将减少或防止替代性巨噬细胞编程，促纤维化生长因子的产生以及与ALI/ARDS相关的副肺纤维化的发展。这些假设将以三个特定的目的来解决。使用小鼠模型中DUSP1表达的遗传和条件操纵，特定目的1的目的是解决以下假设：巨噬细胞的DUSP1表达是纤维增生的ALI所必需的。在特定目标2中，我们将检验以下假设：DUSP1依赖性纤维化肺部疾病是由替代编程的巨噬细胞介导的，产生促纤维化生长因子。最后，在特定目标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，我们将评估当前可用的小分子DUSP1表达抑制剂，目前已批准用于人类使用，因为它们具有表含量DUSP1缺乏症的能力并抑制了小鼠实质肺纤维化的发展。我们提出的研究是首次研究蛋白质磷酸酶是治疗纤维增生ALI的治疗靶标。这是该提案的长期目标是将我们的预期发现转化为对患有纤维化肺部疾病风险的ALD ARDS患者的DUSP1抑制剂的临床试验。此外，DUSP1在其他纤维化肺部疾病中也可能是有效的治疗靶点，例如进行性肺纤维化。