Therapeutic modulation of zinc for lung injury and mechanobiology

锌对肺损伤和机械生物学的治疗调节

• 批准号: 10378503
• 负责人: Rebecca M Baron
• 金额: $ 68.95万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378503
• 关键词: Acute Respiratory Distress Syndrome; Admission activity; Affect; Animals; Anti-Inflammatory Agents; Area; Biological; Biological Markers; Cells; Cessation of life; Chemicals; Clinical; Clinical Data; Clinical Practice Guideline; Clinical Trials; Complex; Confidence Intervals; Critical Illness; Cytoprotection; Data; Development; Dose; Drug Kinetics; Enrollment; Excretory function; Exhibits; Failure; Female; Foundations; Gender; Goals; Heme; Heterogeneity; Host Defense; Human; Immune response; In Vitro; Incidence; Inflammation; Inflammatory; Intervention; Investigation; Life; Lung; Mechanical ventilation; Mechanics; Metabolism; Metallothionein; Modeling; Molecular; Morbidity - disease rate; Mus; Outcome; Oxygenases; Parenteral Nutrition; Pathogenesis; Pathway interactions; Patients; Persons; Pharmacology; Phenotype; Plasma; Population Heterogeneity; Predisposition; Prevalence; Prevention strategy; Randomized Controlled Trials; Recommendation; Regulation; Risk; Safety; Savings; Sepsis; Stretching; Syndrome; Testing; Therapeutic; Time; Tissues; Ventilator-induced lung injury; Zinc; Zinc deficiency; Zinc supplementation; cecal ligation puncture; cell type; clinical research site; clinical translation; cohort; cost; epithelial injury; high reward; human model; human subject; in vivo; indexing; lung injury; male; mortality; mouse model; novel; novel therapeutics; oxidant stress; patient response; phase I trial; preservation; prevent; pulmonary function; response; restoration; septic patients; targeted treatment; therapeutic candidate; treatment strategy; zinc-binding protein

Project Summary The Acute Respiratory Distress Syndrome affects as many as 190,000 people each year and has a mortality rate as high as 46% despite improvement in beside management of mechanical ventilation strategies. There is no specific therapy for ARDS, and novel therapeutic concepts are urgently needed. We have discovered that the zinc-dependent metallothionein pathway exerts anti-inflammatory and cytoprotective effects during cell stretch in vitro and during ventilator-induced lung injury in vivo, and in human subjects with ARDS. Our central hypothesis/premise is that lung stretch initiates zinc-dependent lung protective molecular responses. A key corollary of this hypothesis is that zinc repletion represents a low-risk, high reward therapeutic approach to prevent and/or treat ARDS. However, regulation of zinc stores/metabolism is complex. In particular, low plasma zinc levels do not necessarily reflect low tissue stores of zinc, and there is substantial heterogeneity in zinc metabolism amongst critically ill patients. Thus, tailoring a safe and effective zinc supplementation strategy for ARDS requires mechanistic and clinical data. We propose to examine the biologic and clinical endpoints of zinc deficiency and response to zinc repletion in studies spanning cells to humans. In Aim 1, we will determine the impact of zinc repletion on the response to cell stretch in vitro, examining the pharmacokinetics, time course, and zinc import/export mechanisms underlying zinc repletion using models mirroring human ARDS. In Aim 2, we will determine the effect of chemical rescue of zinc deficiency in response to cell stretch using murine models of human ARDS to examine the pharmacokinetics, time course, dosing strategy/interval, tissue/cellular zinc stores, and underlying mechanism of restoration of zinc deficiency in both male and female mice. In Aim 3, we will determine the incidence and impact of zinc deficiency in human ARDS through a comprehensive analysis of zinc levels in ARDS subjects throughout the course of illness that will enable us to correlate zinc levels with clinical outcomes, as well as biomarkers of inflammation, oxidant stress, epithelial injury, zinc transporter status, and host defense. These studies will reveal, for the first time, the impact of zinc deficiency on the pathogenesis and therapy of ARDS and enable us to determine which patients might benefit from zinc repletion during ARDS. Our long-term goal is to develop the first targeted therapeutic and preventive strategy for ARDS. Importantly a Phase 1 trial recently completed enrollment testing zinc supplementation to augment the immune response in sepsis, providing a foundation for rapid clinical translation of this project.

项目摘要 急性呼吸窘迫综合征每年影响多达19万人，死亡率 尽管机械通气策略的管理旁边有所改善，但利率高达46％。有 迫切需要对ARD的特定疗法和新颖的治疗概念。我们发现 依赖锌的金属硫蛋白途径在细胞过程中发挥抗炎和细胞保护作用 在体外和呼吸机诱导的肺损伤期间，在患有ARDS的受试者中伸展。我们的中心 假设/前提是肺拉伸会引发依赖锌的肺保护性分子反应。钥匙 该假设的推论是，锌的补充代表了一种低风险的高奖励治疗方法 预防和/或治疗ARDS。但是，锌存储/代谢的调节很复杂。特别是低 血浆锌水平不一定反映锌的低组织存储，并且存在很大的异质性 重症患者中的锌代谢。因此，调整安全有效的锌补充 ARDS的策略需要机械和临床数据。我们建议检查生物学和临床 锌缺乏症的终点和对细胞对人类的研究的锌补充的反应。在AIM 1中，我们 将确定锌补充对体外细胞伸展反应的影响，从而检查 使用模型的锌补充的药代动力学，时间课程和锌进出机制 反映人类的ards。在AIM 2中，我们将确定化学挽救锌缺乏症的影响 使用人类ARD的鼠模型对细胞拉伸的反应，以检查药代动力学，时间过程， 剂量策略/间隔，组织/细胞锌存储以及锌缺乏率恢复的潜在机制 在男性和雌性小鼠中。在AIM 3中，我们将确定锌缺乏的发生率和影响 人类通过对整个过程中ARDS受试者的锌水平进行全面分析 将使我们能够将锌水平与临床结果以及炎症的生物标志物相关的疾病 氧化应激，上皮损伤，锌转运蛋白状态和宿主防御。这些研究将揭示，第一个 时间，锌缺乏对ARD的发病机理和治疗的影响，使我们能够确定 哪些患者可能会从ARDS期间的锌补充中受益。我们的长期目标是开发第一个 有针对性的治疗和预防策略。重要的是，最近完成的1阶段试验 补充锌的注册测试以增加败血症的免疫反应，为 该项目的快速临床翻译。