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）：该 K23 职业发展奖的总体目标是熟悉并加深对酒精在潜在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以及酗酒捐赠者的接受者发生慢性排斥反应。在肺移植中，人们对供者酗酒对同种异体肺移植功能的影响知之甚少，因此对受者肺移植结果的影响实际上是未知的。我们的初步数据显示，酒精捐赠者的同种异体肺移植受者的结果明显更差，原发性移植物功能障碍更严重。因此，该项目将为酒精研究和肺移植领域增添新的见解，最终创新性的新预防策略和开发治疗方法来改善该项目产生的肺同种异体移植物，不仅会改善肺移植受者的肺部健康，而且还将显着减少医疗支出。该拟议项目将扩展我们令人信服的初步数据，这些数据表明，接受来自酗酒捐献者的同种异体移植物的肺移植受者的同种异体移植物功能障碍有所增加。移植后早期的肺功能障碍通过长时间使用机械通气和住院治疗而变得明显。酒精捐赠者的受者肺同种异体移植物中的气体交换明显更差。进一步的研究将使我们能够检查慢性酗酒者的同种异体肺移植物在一次饮酒之前、之后和之后所经历的促炎和氧化应激。 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，并且对移植后早期的同种异体移植物功能有害，并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标中进行测试，旨在 1）确定同种异体肺移植供者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、感染的发展和慢性排斥； 3)确定支气管肺泡灌洗液中酒精介导的促炎生物标志物和酒精介导的氧化应激标志物在肺移植的缺血再灌注应激后是否产生过度反应。拟议的研究将确定捐献者酗酒如何影响移植时、移植后立即和移植后长期的同种异体肺移植物。这项研究将为我未来的 R01 应用提供初步证据，根据我在这个拟议项目中的发现，我打算为供体和肺移植受者制定策略和干预措施，以改善同种异体肺移植物的短期和长期功能。如果我们确定 作为潜在的干预目标，我们将计划进行一项多中心临床试验，以确定 suc 干预是否可以改善肺移植后的同种异体移植功能。我的职业目标是开发一个专注于酒精对肺部影响的转化研究项目。具体来说，我将调查人类肺捐赠者的酒精滥用情况，以最终制定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。在研究员期间的实验室、临床和正式课程的基础上，我将接受酒精、免疫学和移植研究方面的强化培训。在我的职业发展计划中，我的培训将包括额外的课程、个人指导和在全国会议上的演讲。我将得到校园里最成功的导师伊丽莎白·科瓦奇博士的指导，此外，我还组建了包括博士在内的咨询委员会。 David Guidot、Ellen Burnham、Carol Schermer 和 Rebecca Shilling 将通过提供职业发展和指导的额外资源来补充 Kovacs 博士的资源。这种环境和指导将确保我成功过渡为独立调查员。该申请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 LUC 为我提供的强大的机构资源和支持。此外，我提出的研究具有创新性，将成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，并实现成为肺酒精研究领导者的目标。