Midcareer Investigator Award in Patient-Oriented Research in Acute Lung Injury

描述(由申请人提供)：这一以患者为中心的研究的职业生涯中期奖的总体目标是使Ware博士能够建立和扩大她在急性肺损伤(ALI)以患者为中心的研究和指导计划。这一奖项将使她能够将更多的时间花在她目前的导师身上，并扩大她的导师范围，将新的博士后实习生以及范德比尔特重点培训计划中的医学生包括在内。此外，这一奖项的支持将使Ware博士担任肺部医学T32临床和转化研究培训计划(NIH 5T32 HL087738)的联席主任。威尔博士的以病人为中心的研究计划将在新的和新的方向上扩展。具体地说，她将建立在器官捐赠者和肺移植后ALI(原发移植物功能障碍，PGD)的研究基础上，以及正在进行的ALI中凝血和纤溶变化的机制作用的研究。PGD对肺移植的发病率、死亡率和费用有重要影响。PGD的研究在ALI研究领域是独一无二的，因为它们有可能确定内在的供体来源的肺因子在ALI发病机制中的影响。这些研究的总体假设是，供体肺的凝血和纤溶级联基因和蛋白水平的改变是肺移植受者PGD的主要决定因素。这一假设将在两个特定目标中进行检验：特定目标1：检验器官捐赠者中常见的凝血和纤溶基因多态性与肺移植受者的临床结果(包括PGD)之间存在显著关联的假设。这些研究还将测试供者血浆中基因蛋白产物水平的相关性，这些基因的多态与更差或更好的临床结果相关。具体目的2：验证器官供者与器官受者相比，凝血和纤溶功能失调对包括PGD在内的受者临床结局有不同贡献的假设。更好地了解供体肺的凝血和纤溶途径对肺移植受者发生PGD的影响，将大大提高我们对ALI发病机制的认识，并最终可能为肺移植受者PGD的预防和治疗以及非移植相关ALI的潜在新疗法提供新的治疗方法。这些研究还可能导致改进供者选择标准和供受者配型，以减少PGD的发生率。通过以患者为中心的研究和训练有素的新一代临床研究人员在ALI实现的对疾病发病机制的更好理解和早期诊断的改进，将加深我们的知识，并为这种每年影响20万美国人、死亡率约为40%的临床疾病开辟新的治疗机会。 公共卫生相关性：PGD的研究在ALI研究领域是独一无二的，因为它们有潜力确定内在的供体来源的肺因子对ALI发病机制的影响。这些研究的总体假设是，供体肺的凝血和纤溶级联基因和蛋白水平的改变是肺移植受者PGD的主要决定因素。

DESCRIPTION (provided by applicant): The overall goal of this Midcareer Investigator Award in Patient-Oriented Research is to enable Dr. Ware to build and expand her research and mentoring programs in patient-oriented research in acute lung injury (ALI). This award will allow her to devote more time to her current mentees as well as to expand her mentoring to include new postdoctoral trainees as well as medical students in the Vanderbilt Emphasis Training Program. In addition, the support of this award will allow Dr. Ware to assume an important role as Co-Director of the T32 Clinical and Translational Research Training Program in Pulmonary Medicine training program (NIH 5T32 HL087738). Dr. Ware's program in patient-oriented research will be expanded in new and novel directions. Specifically, she will build on studies of organ donors and ALI (primary graft dysfunction, PGD) after lung transplantation, as well as ongoing studies of the mechanistic role of alterations in coagulation and fibrinolysis in ALI. PGD has a major impact on morbidity, mortality and cost of lung transplantation. Studies of PGD are unique in the field of ALI research in their potential to determine the impact of intrinsic donor-derived lung factors on the pathogenesis of ALI. The overall hypothesis of the proposed studies is that alterations in the coagulation and fibrinolytic cascades at both the genetic and protein level in the donor lung are major determinants of PGD in the lung allograft recipient. This hypothesis will be tested in two specific aims: Specific Aim 1: To test the hypothesis that there is a significant association between common polymorphisms in coagulation and fibrinolysis genes in the organ donor and clinical outcomes in the lung transplant recipient, including PGD. These studies will also test the association of donor plasma levels of the protein products of the genes whose polymorphisms are associated with worse or better clinical outcomes. Specific Aim 2: To test the hypothesis that there is a differential contribution of dysregulated coagulation and fibrinolysis in organ donors compared to organ recipients to recipient clinical outcomes including PGD. A better understanding of the influence of the coagulation and fibrinolytic pathways in the donor lung on subsequent development of PGD in the lung recipient will significantly enhance our understanding of the pathogenesis of ALI and may ultimately lead to new therapies for prevention and treatment of PGD in lung transplant recipients as well as potential new therapies for non-transplant associated ALI. These studies may also lead to improved donor selection criteria and donor-recipient matching to reduce the incidence of PGD. The better understanding of disease pathogenesis and improved early diagnosis that will be realized through patient-oriented research and a well trained new generation of clinical researchers in ALI will deepen our knowledge and open up new therapeutic opportunities for this clinical disorder that affects 200,000 Americans annually with a mortality rate of approximately 40%. PUBLIC HEALTH RELEVANCE: Studies of PGD are unique in the field of ALI research in their potential to determine the impact of intrinsic donor-derived lung factors on the pathogenesis of ALI. The overall hypothesis of the proposed studies is that alterations in the coagulation and fibrinolytic cascades at both the genetic and protein level in the donor lung are major determinants of PGD in the lung allograft recipient.