Phosphorylation Control of Fibroproliferative ARDS

纤维增殖性 ARDS 的磷酸化控制

• 批准号: 10171609
• 负责人: Yael Aschner
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171609
• 关键词: Accounting; Acute; Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Affect; Alleles; Alveolar; Animal Model; Attenuated; Basic Science; Biological; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cell membrane; Cells; Cessation of life; Clinical; Clinical Sciences; Colorado; Critical Care; Data; Dependence; Deposition; Development; Development Plans; Educational workshop; Environment; Epithelial Cells; Extracellular Matrix; Failure; Fibroblasts; Fibrosis; Future; Genetic; Genetic Transcription; Goals; Health Care Costs; Healthcare; Human; Hydrochloric Acid; Impaired health; Impairment; In Vitro; Inflammation; Influenza; Influenza A Virus, H1N1 Subtype; Injury; Intervention; Investigation; Knock-out; Knowledge; Leadership; Learning; Length of Stay; LoxP-flanked allele; Lung; Lung diseases; MAP Kinase Gene; Mediating; Medicine; Mentorship; Modeling; Monoclonal Antibodies; Mus; Myofibroblast; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Pharmacology; Phase; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Positioning Attribute; Protein Inhibition; Protein Tyrosine Phosphatase; Pulmonary Fibrosis; Regulation; Research; Research Personnel; Risk; Role; Science; Scientist; Side; Signal Pathway; Signal Transduction; Supportive care; Survivors; Testing; Therapeutic; Training Programs; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Transgenic Mice; Translating; Translational Research; United States; Universities; Ventilator; Work; career development; cell type; clinically relevant; experience; experimental study; fibrogenesis; health related quality of life; improved outcome; in vivo Model; inhibitor/antagonist; innovation; lung injury; mortality; mouse model; novel; patient subsets; preservation; prevent; professor; prognostic; prospective; receptor; response; single-cell RNA sequencing; skills; src-Family Kinases; therapy development; transcriptomics; translational physician

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.

项目概要 该提案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 急性肺损伤后致病性肺纤维化的发展候选人是助理。 科罗拉多大学呼吸科学和重症监护科医学教授 概述的提案建立在她强大的基础科学研究背景之上，并开发了新的内容。 格雷戈里·唐尼博士和艾伦·伯纳姆博士的指导下的转化研究技能。 研究计划、教学、实践研讨会和实习学习将为候选人提供独特的能力 一套跨学科技能将使她能够过渡到独立作为基础和转化 肺损伤和纤维化领域的医师科学家。 急性呼吸窘迫综合征 (ARDS) 是美国许多 ARDS 幸存者的一个主要医疗保健问题。 由于病理性肺纤维增生的发展，长期结果受到损害。 过度纤维增殖，称为纤维增殖性ARDS（FP-ARDS），其特征是早期、过度 旺盛的纤维增殖反应伴随肌成纤维细胞的积累和细胞外基质的沉积， 部分归因于 TGF-β 的增加，预测有发生 FP-ARDS 风险的患者的能力将有助于 预测、针对性干预措施以及特定疗法的开发。 蛋白酪氨酸磷酸酶（PTP）-α是一种广泛表达的受体型酪氨酸磷酸酶。 PTPα (Ptpra-/-) 遗传缺陷在肺纤维化模型中通过影响机制受到保护 细胞对 TGF-β 的反应 该提案将评估 PTPα 在 FP-ARDS 发病机制中的作用。 并检验以下假设：抑制 PTPα 将通过减弱 候选人将解决成纤维细胞中的 TGF-β 信号的三个主要研究目标。 PTPα 是否是 FP-ARDS 小鼠模型（包括体内）纤维增殖反应所必需的。 气管盐酸和 H1N1 流感将用于确定 PTPα 的遗传缺失是否提供 细胞类型特异性敲除 PTPα 将进一步有助于防止纤维增殖的发生。 描述 PTPα 在关键肺实质细胞中的作用特定目标 2 的目标是更好地进行研究。 PTPα 促进肺成纤维细胞促纤维化途径的细胞机制 特别关注 TGF-β 受体和 Src 激酶的先前和前瞻性影响。 收集人支气管肺泡灌洗（BAL）液，以更好地量化肺部促纤维化环境 ARDS 患者并确定 PTPα 是否会增强这些纤维增殖反应。 表征细胞对人 ARDS BAL 的促纤维化反应，并将这些反应与长期 ARDS 患者的长期临床过程该提案的长期目标是转化我们的预期发现。 参与 ARDS 患者治疗方法的开发。