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

描述（由申请人提供）：这项以患者为导向的研究中期研究者奖的总体目标是使Ware博士能够建立和扩大她在急性肺损伤（ALI）以患者为导向的研究中的研究和指导计划。这个奖项将使她能够投入更多的时间，她目前的学员，以及扩大她的指导，包括新的博士后学员以及医学生在范德比尔特强调培训计划。此外，该奖项的支持将使Ware博士能够担任T32临床和转化研究培训项目（NIH 5 T32 HL 087738）的联合主任。威尔博士在以病人为导向的研究计划将在新的和新颖的方向扩大。具体来说，她将建立在肺移植后器官供体和ALI（原发性移植物功能障碍，PGD）的研究，以及正在进行的ALI凝血和纤溶改变的机制作用的研究。PGD对肺移植的发病率、死亡率和费用有重大影响。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供体来源的肺因子对ALI发病机制的影响。所提出的研究的总体假设是，在供体肺中的遗传和蛋白质水平上的凝血和纤溶级联的改变是肺同种异体移植物受体中PGD的主要决定因素。将在两个具体目标中检验该假设：具体目标1：检验器官供体中凝血和纤溶基因的常见多态性与肺移植受者的临床结局（包括PGD）之间存在显著关联的假设。这些研究还将测试其多态性与更差或更好的临床结果相关的基因的蛋白质产物的供体血浆水平的关联。具体目标二：检验器官供体与器官受体相比，凝血和纤溶失调对受体临床结局（包括PGD）的贡献不同的假设。更好地了解供体肺中凝血和纤溶途径对肺受体中PGD后续发展的影响将显著增强我们对ALI发病机制的理解，并可能最终导致预防和治疗肺移植受体中PGD的新疗法以及非移植相关ALI的潜在新疗法。这些研究也可能导致改善供体选择标准和供体-受体匹配，以减少PGD的发生率。通过以患者为导向的研究和训练有素的新一代临床研究人员在ALI中实现对疾病发病机制的更好理解和改进的早期诊断，将加深我们的知识，并为这种临床疾病开辟新的治疗机会，每年影响20万美国人，死亡率约为40%。 公共卫生相关性：PGD的研究在ALI研究领域是独一无二的，因为它们有可能确定内在供体来源的肺因子对ALI发病机制的影响。所提出的研究的总体假设是，在供体肺中的遗传和蛋白质水平上的凝血和纤溶级联的改变是肺同种异体移植物受体中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.