Phosphorylation Control of Fibroproliferative ARDS

纤维增殖性 ARDS 的磷酸化控制

• 批准号: 10624256
• 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/10624256
• 关键词: Accounting; Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; 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 fibrogenesis; MAP Kinase Gene; Mediating; Medicine; Mentorship; Modeling; Monoclonal Antibodies; Mus; Myofibroblast; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Persons; Phase; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Positioning Attribute; Profibrotic signal; 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; fibrotic lung disease; health related quality of life; improved outcome; in vivo Model; inhibitor; innovation; lung injury; mortality; mouse model; novel; patient subsets; pharmacologic; preservation; prevent; professor; prognostication; 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 该建议代表了一项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发生的发展。候选人是助手 科罗拉多大学肺科学和重症监护系的医学教授 药品。概述的提案以她在基础科学研究中的强大背景为基础，并开发了新的 DRS心态下的翻译研究技能。格雷戈里·唐尼（Gregory Downey）和艾伦·伯纳姆（Ellen Burnham）。提议 研究计划，教学计划，动手研讨会和板凳侧学习将使候选人为独特 一套跨学科技能，将使她的过渡到独立性，成为基本和翻译 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）是美国的主要医疗问题。许多ARDS幸存者 由于病理肺纤维增殖的发展，经验损害了长期结局。这 过多的纤维增殖，称为纤维增生ARDS（FP-ARD），其特征是早期，过度 肌纤维细胞积累和细胞外基质的沉积，良好的纤维增生反应， 部分原因是TGF-β的增加。预测患有开发FP-ald风险的患者的能力将有助于 预后，靶向干预措施以及特定疗法的发展。 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。老鼠 在肺纤维化模型中通过影响的机制保护了遗传缺乏PTPα（PTPRA - / - ） 细胞对TGF-β的反应能力。该提案将评估PTPα在FP-pard的发病机理中的作用 并检验抑制PTPα的假设将通过衰减来防止ARDS中的病理纤维增殖 成纤维细胞中的TGF-β信号。候选人将解决三个主要研究目的。特定目标1将重点放在 是否需要PTPα进行ARDS中的纤维增生反应。 fp-pard的鼠模型，包括 气管盐酸和H1N1影响力将用于确定PTPα的遗传缺失是否提供 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 表征PTPα在关键肺实质细胞中的作用。特定目标2的目标是更好 了解PTPα促进肺成纤维细胞中的纤维细胞途径的细胞机制， 特别关注TGF-β受体和SRC激酶。特定目标3先前且前瞻性 收集的人支气管肺泡灌洗（BAL）流体，以更好地量化 ARDS患者并确定PTPα是否增加了这些纤维增生反应。体外实验将 表征了对人Ards BAL的细胞纤维纤维化反应，并将这些反应与长期相关 ARDS患者的术语临床过程。该提议的长期目标是翻译我们的预期发现 进入针对ARDS患者的疗法发展。