Phosphorylation Control of Fibroproliferative ARDS

项目总结 这项建议代表了一项为期五年的研究职业发展计划，旨在更好地了解 急性肺损伤后病理性肺纤维化的进展。应聘者是助理 科罗拉多大学肺科学和重症监护科医学教授 医学。概述的建议建立在她在基础科学研究方面的强大背景之上，并开发了新的 Gregory Downey博士和Ellen Burnham博士指导下的翻译研究技能。建议数 研究计划、教学、实践研讨会和板凳学习将使应聘者获得独特的 一套跨学科的技能，使她能够过渡到独立的基础和翻译 内科医生--肺损伤和纤维化领域的科学家。 急性呼吸窘迫综合征(ARDS)是美国的一个主要医疗问题。许多ARDS幸存者 经历由于病理性肺纤维增生的发展而损害的长期结果。这 纤维过度增生，称为纤维增生性ARDS(FP-ARDS)，其特征是早期、过度 随着肌成纤维细胞的聚集和细胞外基质的沉积，旺盛的纤维增殖反应， 部分原因是转化生长因子-β的增加。预测有患FP-ARDS风险的患者的能力将有助于 预测、针对性干预和特定疗法的发展。 蛋白酪氨酸磷酸酶-α是一种广泛表达的受体型酪氨酸磷酸酶。老鼠 在肺纤维化模型中，遗传缺陷的Ptpα(Ptpra-/-)通过作用机制受到保护 细胞对转化生长因子-β的反应性。这项建议将评估pTPα在FP-ARDS发病机制中的作用 并验证了抑制ptpα将通过减弱 成纤维细胞中的转化生长因子-β信号。候选人将提出三个主要研究目标。具体目标1将重点放在 急性呼吸窘迫综合征的纤维增殖性反应是否需要ptpα。FP-ARDS小鼠模型，包括Intra-ARDS 将利用气管盐酸和H1N1流感来确定遗传缺失的ptpα是否会提供 防止纤维增殖的发展。PtPα的细胞类型特异性敲除将进一步有助于 研究ptpα在关键肺实质细胞中的作用。具体目标2的目标是更好地 了解ptpα促进肺成纤维细胞纤维化途径的细胞机制 特别关注转化生长因子-β受体和src激酶。之前和预期的特定目标3杠杆作用 收集人支气管肺泡灌洗液(BAL)以更好地量化肺组织中的促纤维化环境 ARDS患者，并确定ptpα是否增强这些纤维增殖反应。体外实验将会 描述对人ARDS BAL的细胞促纤维化反应，并将这些反应与长期... ARDS患者的长期临床病程。这项提议的长期目标是将我们预期的发现转化为 为ARDS患者开发治疗方法。

PROJECT SUMMARY This proposal represents a five-year research career development plan aimed at better understanding the development of pathogenic pulmonary fibrogenesis following acute lung injury. The candidate is an Assistant Professor of Medicine at the University of Colorado in the Division of Pulmonary Sciences and Critical Care Medicine. The outlined proposal builds on her strong background in basic science research and develops new translational research skills under the mentorship of Drs. Gregory Downey and Ellen Burnham. The proposed research plan, didactics, hands-on workshops, and bench-side learning will position the candidate with a unique set of cross-disciplinary skills that will enable her transition to independence as a basic and translational physician-scientist in the fields of lung injury and fibrosis. The acute respiratory distress syndrome (ARDS) is a major healthcare problem in the US. Many ARDS survivors experience impaired long-term outcomes due to the development of pathologic pulmonary fibroproliferation. This excessive fibroproliferation, termed fibroproliferative ARDS (FP-ARDS), is characterized by early, over- exuberant fibroproliferative responses with accumulation of myofibroblasts and deposition of extracellular matrix, due in part to increases in TGF-β. The ability to predict patients at risk for developing FP-ARDS will assist with prognostication, targeting interventions, and the development of specific therapies. Protein Tyrosine Phosphatase (PTP)-α is a widely expressed receptor-type tyrosine phosphatase. Mice genetically deficient in PTPα (Ptpra-/-) are protected in models of pulmonary fibrosis via mechanisms affecting cellular responsiveness to TGF-β. This proposal will evaluate the role of PTPα in the pathogenesis of FP-ARDS and test the hypothesis that inhibition of PTPα will prevent pathologic fibroproliferation in ARDS by attenuating TGF-β signals in fibroblasts. The candidate will address three main research aims. Specific Aim 1 will focus on whether PTPα is required for fibroproliferative responses in ARDS. Murine models of FP-ARDS, including intra- tracheal hydrochloric acid and H1N1 influenza will be utilized to determine if genetic absence of PTPα provides protection from the development of fibroproliferation. Cell-type specific knockout of PTPα will further assist in characterizing the role PTPα plays in key lung parenchymal cells. The goal of Specific Aim 2 is to better understand the cellular mechanisms by which PTPα promotes profibrotic pathways in lung fibroblasts, with a particular focus on TGF-β receptors and Src kinase. Specific Aim 3 leverages previously and prospectively collected human bronchoalveolar lavage (BAL) fluid to better quantify the profibrotic environment in the lungs of ARDS patients and determine if PTPα augments these fibroproliferative responses. In vitro experiments will characterize cellular profibrotic responses to human ARDS BAL and correlate these responses with the long- term clinical course of ARDS patients. A long-term goal of this proposal is to translate our anticipated findings into the development of therapies for patients with ARDS.