DUSP1 as a therapeutic target in fibroproliferative acute lung injury

描述(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)，是一种严重的疾病，总死亡率高达约25%，令人无法接受。此外，一些患者会发展成一种叫做纤维增生性ALI的衰弱、持续性、有时甚至是致命的纤维性肺病。不幸的是，目前还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特异性蛋白磷酸酶-1(DUSP1，又名MKP-1)的作用来满足这一治疗需求。DUSP1是一种苏氨酸/酪氨酸磷酸酶，可使丝裂原激活的蛋白激酶p38和JNK去磷酸化和失活。在使用小鼠急性肺损伤和纤维化模型的初步研究中，我们已经表明，在缺乏DUSP1的小鼠中，肺纤维化的发展是消融的。我们的初步研究还表明，小鼠的DUSP1基因缺陷会损害巨噬细胞进行“替代”编程的能力，导致包括转化生长因子-β在内的促纤维化生长因子的产生受损。这些和其他方面的考虑使我们假设DUSP1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相关的实质肺纤维化的发展。这些假设将以三个具体目标加以阐述。利用小鼠模型中DUSP1表达的遗传和条件操作，特异性目标1的目标是解决巨噬细胞DUSP1表达是发展成纤维增生性ALI所必需的假说。在特定的目标2中，我们将检验DUSP1依赖的纤维性肺病是由产生促纤维化生长因子的交替编程的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 通过开展临床前研究，我们将评估目前已批准用于人类的两种小分子DUSP1表达抑制剂的表型复制DUSP1缺乏症和抑制小鼠肺实质纤维化发展的能力。我们提出的研究是首次将蛋白磷酸酶作为治疗纤维增生性ALI的靶点进行研究。因此，这项建议的长期目标是将我们预期的发现转化为DUSP1抑制剂在ALI和ARDS患者中的临床试验，这些患者有发展成纤维化肺部疾病的风险。此外，DUSP1也可能是其他纤维化肺疾病的有效治疗靶点，例如进行性肺纤维化。

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.