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: 9221936
• 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/9221936
• 关键词: Acute; Acute Lung Injury; Advisory Committees; Affect; Alcohol abuse; Alcohol consumption; Alcohols; Allografting; Area; Award; Biological Markers; Brain Death; Bronchiolitis Obliterans; Bronchoalveolar Lavage Fluid; Chronic; Clinical; Committee Members; Complement; Complication; Data; Development; Development Plans; Ensure; Environment; Epidemiology; Epithelial; Expenditure; Fellowship; Foundations; Functional disorder; Future; Gases; Goals; Health; Healthcare; Hospitalization; Human; Immunology; Individual; Infection; Inflammatory; Injury; 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; Morbidity - disease rate; Multi-Institutional Clinical Trial; Organ Donor; Organ Transplantation; Outcome; Oxidative Stress; Patients; Perioperative; Physiology; Prevention strategy; Preventive Intervention; Process; Reactive Oxygen Species; Recording of previous events; Reperfusion Therapy; Research; Research Personnel; Resources; Respiratory physiology; Risk; Role; Solid; Source; Stress; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Transplant Recipients; Transplantation; Vulnerable Populations; alcohol effect; alcohol epidemiology; alcohol misuse; alcohol research; alcohol risk; base; career; career development; chronic alcohol ingestion; conditioning; design; experience; high risk; high risk behavior; improved; improved outcome; inflammatory milieu; innovation; insight; lung allograft; meetings; mortality; novel; organ allocation; problem drinker; public health relevance; response; skills; therapeutic development; translational research program; virtual

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）：该K23职业发展奖的总体目标是熟悉并更好地了解酒精对潜在机制的作用，这些机制可能加速移植物功能障碍和酗酒供体受体慢性排斥反应的发展。在肺移植中，关于供体酗酒对肺移植功能的影响知之甚少，因此对受体肺移植结果的后果几乎是未知的。我们的初步数据显示，来自酗酒供体的肺同种异体移植物的受者的结果明显更差，原发性移植物功能障碍的发展更严重。因此，该项目将为酒精研究和肺移植领域增加新的见解，最终创新的新预防策略和治疗方法的开发，以改善该项目产生的肺移植物，不仅可以改善肺移植受者的肺健康，而且还可以显着降低医疗费用。这个建议的项目将扩大我们令人信服的初步数据表明，在肺移植受者接受同种异体移植物与酗酒的捐助者增加同种异体移植物功能障碍。移植后早期的肺功能障碍通过长期使用机械通气和住院治疗而明显。酒精供体的肺移植物的气体交换明显变差。进一步的研究将使我们能够检查慢性酒精中毒者肺移植前、移植后和移植后的促炎和氧化应激。 肺移植后一年。我们的假设是，供体酒精的使用对移植中的人肺同种异体移植物有负面影响，并且在移植后早期对同种异体移植物功能有害，并且随后导致慢性排斥反应增加，称为闭塞性细支气管炎综合征。我们的假设将在特定目的中进行检验，目的是1）确定肺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，如急性排斥反应，感染和慢性排斥反应的发生;和3）确定是否酒精介导的前-支气管肺泡灌洗液中的炎性生物标志物和酒精介导的氧化应激标志物在局部缺血后产生过度反应，肺移植再灌注应激。拟议的研究将确定供体中的酒精滥用如何影响移植时的肺移植物，移植后立即和移植后长期。这项研究将为我未来的R 01应用提供初步证据，根据我在这个拟议项目中的发现，我打算在供体和肺移植受者中制定策略和干预措施，以改善肺移植物的短期和长期功能。如果我们确定 作为一个潜在的干预目标，我们将计划一个多中心的临床试验，以确定肺移植后的移植物功能是否可以改善。我的职业目标是发展一个转化研究项目，重点是酒精对肺部的影响。具体来说，我将调查人类肺供体酒精滥用的预防和治疗干预措施，以改善肺移植后的器官分配和同种异体移植功能的最终发展。在奖学金期间的实验室，临床和正式课程的基础上，我将接受酒精，免疫学和移植研究的强化培训。在我的职业发展计划中，我的培训将包括额外的课程，个人指导和在国家会议上的演讲。我将接受校园里最成功的导师伊丽莎白·科瓦奇博士的指导，此外，我召集的咨询委员会，包括大卫·吉多博士、埃伦·伯纳姆博士、卡罗尔·舍默博士和丽贝卡·希林博士，将通过提供职业发展和指导的额外资源来补充科瓦奇博士的资源。这种环境和指导将确保我成功地过渡到一个独立的调查员。这个应用程序的优势包括我全面的职业发展计划，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，以及强大的机构资源和支持LUC提供给我。此外，我提出的研究是创新的，将作为我独立职业发展的跳板。在K23奖的支持下，我将获得实现独立所需的经验和技能，以及成为肺部酒精研究领导者的目标。