Alcohol and Lung Transplantation: Understanding donor and recipient consequences

酒精和肺移植：了解捐赠者和接受者的后果

• 批准号: 8792823
• 负责人: Erin Lowery
• 金额: $ 18.1万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792823
• 关键词: Abbreviations; Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Advisory Committees; Affect; Alanine Transaminase; Alcohol abuse; Alcohol consumption; Alcohols; Allografting; Area; Aspartate Transaminase; Award; Biological Markers; Brain Death; Bronchiolitis Obliterans; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; CCL2 gene; CSF3 gene; CXC chemokine IP-10; CXCL10 gene; Chicago; Chronic; Clinical; Committee Members; Complement; Complication; Data; Development; Development Plans; Ensure; Environment; Epidemiology; Epithelial; Expenditure; Fellowship; Fibroblast Growth Factor; Foundations; Functional disorder; Future; Gamma-glutamyl transferase; Gases; Goals; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Healthcare; Hospitalization; Human; Immunology; Individual; Infection; Inflammatory; Injury; Interferon Type II; Interferons; Interleukins; Intervention; Investigation; Ischemia; K-Series Research Career Programs; Laboratories; Life; Long-Term Effects; Lung; Lung Transplantation; Lung diseases; Mechanical ventilation; Mediating; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Monocyte Chemoattractant Protein-1; Morbidity - disease rate; Multi-Institutional Clinical Trial; Organ Donor; Organ Procurements; Organ Transplantation; Outcome; Oxidative Stress; Patients; Perioperative; Physiology; Platelet-Derived Growth Factor; Process; RANTES; Reactive Oxygen Species; Recording of previous events; Reperfusion Therapy; Research; Research Personnel; Resources; Risk; Role; Solid; Solutions; Source; Staging; Stress; Syndrome; T-Lymphocyte; TNF gene; Testing; Therapeutic Intervention; Time; Training; Transforming Growth Factor beta; Translational Research; Transplant Recipients; Transplantation; Trypsin; Tumor Necrosis Factor-alpha; United Network for Organ Sharing; Universities; Vascular Endothelial Growth Factors; Vulnerable Populations; alcohol effect; alcohol misuse; alcohol research; base; career; career development; chronic alcohol ingestion; conditioning; design; experience; high risk; high risk behavior; improved; innovation; insight; lung allograft; meetings; mortality; novel; organ allocation; problem drinker; programs; response; skills; therapeutic development

DESCRIPTION (provided by applicant): The overall goal of this K23 Career Development Award is to become familiar with and enable improved understanding of alcohol's role on underlying mechanisms which may accelerate allograft dysfunction and the development of chronic rejection in recipients of donors with alcohol abuse. In lung transplantation, little is known about the influence of donor alcohol abuse on lung allograft function, and therefore the consequences to the recipient's lung transplant outcomes are virtually unknown. Our preliminary data revealed strikingly worse outcomes and more severe development of primary graft dysfunction in recipients of lung allografts from alcoholic donors. Thus, this project would add novel insights to the fields of alcohol research and lung transplantation, and ultimately innovative new preventative strategies and development of therapeutics to improve lung allografts resulting from this project would not only improve lung health in lung transplant recipients, but would also significantly decrease healthcare expenditures. This proposed project will extend our compelling preliminary data demonstrating increased allograft dysfunction in lung transplant recipients who receive allografts from donors with alcohol abuse. Lung dysfunction early after transplant is evident by prolonged use of mechanical ventilation and hospitalizations. Gas exchange in the lung allograft is markedly worse in those recipients with alcoholic donors. Further research will enable us to examine the pro-inflammatory and oxidative stresses experienced by lung allografts of chronic alcoholics prior to, immediately following, and after one year following lung transplantation. Our hypothesis is that donor alcohol use has negative effects on the human lung allograft in transplantation and is detrimental to allograft function bot early following transplant, and later leading to increased chronic rejection, known as bronchiolitis obliterans syndrome. Our hypothesis will be tested in Specific Aims designed to 1) determine the epidemiology of alcohol use and abuse in donors of lung allografts, 2) examine effects on lung transplant outcomes such as acute rejection, development of infections and chronic rejection; and 3) determine whether alcohol mediated pro-inflammatory biomarkers and alcohol mediated oxidative stress markers in bronchoalveolar lavage fluid develop exaggerated responses after the ischemia-reperfusion stresses of lung transplantation. The proposed studies will determine how alcohol abuse in donors effects the lung allograft at the time of transplant, immediately following transplant and long-term following transplant. This research will provide preliminary evidence for my future R01 application, where, based on my findings in this proposed project, I intend to develop strategies and interventions in donors and lung transplant recipients for improvement in short and long-term functioning of the lung allograft. If we identify a potential target for intervention, we will plan a multi-center clinical trial to determine if suc intervention improves allograft function following lung transplantation. My career goal is to develop a translational research program focusing on the pulmonary effects of alcohol. Specifically, I will investigate human lung donor alcohol abuse for eventual development of preventative and therapeutic interventions to improve organ allocation and allograft function following lung transplantation. Building on a foundation of laboratory, clinical and formal coursework during fellowship, I will undergo intensive training in alcohol, immunology and transplant research. Outlined in my career development plan, my training will include additional coursework, individual mentorship, and presentations at national meetings. I will be mentored by the most successful mentor on campus, Dr. Elizabeth Kovacs, and in addition, the Advisory Committee I have assembled, including Drs. David Guidot, Ellen Burnham, Carol Schermer, and Rebecca Shilling, will complement Dr. Kovacs' resources by providing additional sources for career development and mentoring. This environment and mentorship will ensure my successful transition into an independent investigator. The strengths of this application include my comprehensive career development plan, the novel research hypothesis and design, the experience and commitment of my mentor and Advisory Committee members, and the strong institutional resources and support available to me at LUC. In addition, my proposed research is innovative and will serve as a launching pad for the development of my independent career. With the support of the K23 Award, I will gain the experience and skills required to achieve independence and my goal of becoming a leader in pulmonary alcohol research.

描述（由申请人提供）：这一K23职业发展奖的总体目标是熟悉并能够提高对酒精在基本机制中的作用的了解，这些机制可能会加速同种异体移植功能障碍，并在接受酒精滥用的捐助者的接受者中发展慢性拒绝。在肺移植中，对供体酗酒对肺同种异体移植功能的影响知之甚少，因此对接受者肺移植预后的后果几乎是未知的。我们的初步数据表明，在酒精供体的肺同种异体移植物受体中，预后的结果明显更严重，并且更严重地发育。因此，该项目将为酒精研究和肺移植的领域增添新的见解，并最终创新的新预防策略和开发治疗疗法以改善该项目导致的肺同种异体移植物，这不仅会改善肺移植接受者的肺健康状况，而且还将大大降低医疗支出。该拟议的项目将扩展我们引人注目的初步数据，表明在肺移植受者中同种异体功能障碍增加，这些接受者接收来自酗酒的捐助者的同种异体移植物。长时间使用机械通气和住院治疗可以明显看出移植后肺部功能障碍。对于那些接受酒精供体的接受者，肺同种异体移植中的气体交换明显更糟。进一步的研究将使我们能够检查慢性酗酒者肺同种异体移植物所经历的促炎和氧化应激，然后立即，之后和之后 肺移植后的一年。我们的假设是，供体饮酒对移植中的人类肺同种异体移植具有负面影响，并且在移植后早期对同种异体移植功能有害，后来导致慢性排斥力增加，称为延性细支气管炎，称为细支气管炎。我们的假设将在旨在的特定目的中进行检验1）确定肺同种异体移植供体中酒精使用和滥用的流行病学，2）检查对肺移植结果的影响，例如急性排斥，感染和慢性排斥； 3）确定酒精介导的促炎生物标志物和酒精介导的支气管肺泡灌洗液中的氧化应激标志物是否在肺移植的缺血 - 重新灌注应力后会产生夸张的反应。拟议的研究将确定供体中的酗酒在移植时如何影响肺同种异体移植后，在移植后立即进行移植后。这项研究将为我的未来R01应用提供初步证据，根据我在拟议项目中的发现，我打算开发供体和肺移植受者的策略和干预措施，以改善肺同种异体移植的短期和长期运作。如果我们识别 一个潜在的干预目标，我们将计划一项多中心临床试验，以确定肺移植后SUC的干预是否可以改善同种异体移植功能。我的职业目标是制定一项侧重于酒精肺影响的转化研究计划。具体而言，我将研究人类肺供体滥用酗酒，以最终开发预防和治疗性干预措施，以改善肺移植后的器官分配和同种异体移植功能。我将在研究金期间的实验室，临床和正式课程的基础上进行，我将接受酒精，免疫学和移植研究的深入培训。在我的职业发展计划中概述了我的培训将包括其他课程，个人指导和在国家会议上的演讲。我将受到校园中最成功的导师伊丽莎白·科瓦克斯（Elizabeth Kovacs）的指导，此外，我还参加了包括博士在内的咨询委员会。 David Guidot，Ellen Burnham，Carol Schermer和Rebecca Shilling将通过为职业发展和指导提供其他资源来补充Kovacs博士的资源。这种环境和指导将确保我成功地过渡到独立研究者。该申请的优势包括我的全面职业发展计划，新颖的研究假设和设计，我的导师和咨询委员会成员的经验和承诺以及LUC提供的强大机构资源和支持。此外，我拟议的研究具有创新性，并将作为我独立职业发展的发射台。在K23奖的支持下，我将获得实现独立性所需的经验和技能，以及成为肺饮酒研究领导者的目标。