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

描述（由申请人提供）：这个面向患者研究的职业中期研究者奖的总体目标是使Ware博士能够在急性肺损伤（ALI）的面向患者的研究中建立和扩展她的研究和指导计划。这个奖项将使她能够把更多的时间花在她现在的学生身上，并扩大她的指导范围，包括新的博士后学员和范德比尔特重点培训项目的医学院学生。此外，该奖项的支持将使Ware博士担任肺医学培训项目（NIH 5T32 HL087738） T32临床和转化研究培训项目联合主任的重要角色。韦尔博士的以患者为导向的研究项目将向新的和新颖的方向扩展。具体来说，她将建立在器官供体和肺移植后ALI（原发性移植物功能障碍，PGD）的研究，以及正在进行的凝血和纤维蛋白溶解改变在ALI中的机制作用的研究。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供体来源的肺因子对ALI发病机制的影响。提出的研究的总体假设是，在遗传和蛋白质水平上，供体肺的凝血和纤溶级联的改变是肺移植受体PGD的主要决定因素。这一假设将在两个特定目标中得到验证：特定目标1：验证器官供体中凝血和纤溶基因的常见多态性与肺移植受体（包括PGD）的临床结果之间存在显著关联的假设。这些研究还将测试供体血浆中基因蛋白产物水平的相关性，这些基因的多态性与临床结果的好坏有关。具体目的2：验证器官供体与器官受者凝血和纤溶异常对包括PGD在内的受者临床结果的差异贡献的假设。更好地了解供肺凝血和纤溶途径对肺受体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PGD的新疗法，以及潜在的非移植相关ALI的新疗法。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ALI临床研究人员将实现对疾病发病机制的更好理解和改进的早期诊断，这将加深我们的知识，并为这种每年影响20万美国人的临床疾病开辟新的治疗机会，死亡率约为40%。

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.