Phosphorylation Control of Fibroproliferative ARDS

纤维增殖性 ARDS 的磷酸化控制

• 批准号: 9981815
• 负责人: Yael Aschner
• 金额: $ 16.18万
• 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/9981815
• 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.

项目摘要 该提案是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 科罗拉多大学肺科学和重症监护部医学教授 药概述的建议建立在她在基础科学研究的强大背景，并开发新的 在格雷戈里唐尼和埃伦伯纳姆博士的指导下，转化研究技能。拟议 研究计划，教学法，实践研讨会和板凳边学习将定位候选人与独特的 一套跨学科的技能，这将使她过渡到独立的基本和翻译 肺损伤和纤维化领域的医生兼科学家。 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 由于病理性肺纤维增生的发展而经历受损的长期结果。这 过度的纤维增生，称为纤维增生性ARDS（FP-ARDS），其特征在于早期、过度、 伴随肌成纤维细胞积累和细胞外基质沉积的旺盛的纤维增生反应， 部分原因是TGF-β的增加。预测有发生FP-ARDS风险的患者的能力将有助于 精确化、靶向干预和特定疗法的开发。 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。小鼠 PTPα基因缺陷（Ptpra-/-）在肺纤维化模型中通过影响 细胞对TGF-β的反应性。本研究旨在探讨PTPα在FP-ARDS发病机制中的作用 并验证了抑制PTPα可通过减弱肺纤维化而防止ARDS中病理性纤维增生的假设。 成纤维细胞中的TGF-β信号。候选人将解决三个主要的研究目标。具体目标1将侧重于 PTPα是否是ARDS中纤维增生反应所必需的。FP-ARDS的小鼠模型，包括 将使用气管盐酸和H1N1流感病毒来确定PTPα的遗传缺失是否提供 防止纤维增生的发展。PTPα的细胞类型特异性敲除将进一步有助于 表征PTPα在关键肺实质细胞中的作用。第二个目标是更好地 了解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。具体目标3利用以前和前瞻性 收集人支气管肺泡灌洗液（BAL），以更好地量化肺中的促纤维化环境， 并确定PTPα是否增强这些纤维增生反应。体外实验将 表征对人ARDS BAL的细胞促纤维化反应，并将这些反应与长- 急性呼吸窘迫综合征患者的临床病程。这项提案的一个长期目标是将我们的预期发现转化为 为ARDS患者开发治疗方法。