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

 描述（由申请人提供）：本次更新申请的总体目标是在以患者为导向的研究中获得职业中期研究者奖，以使Ware博士能够继续建立和扩大她在以患者为导向的ARDS研究中的研究和指导计划。该奖项将使她能够继续将大量受保护的时间投入到她目前的学员身上，并将她的指导范围扩大到包括新的博士后学员和医学生。此外，该奖项的支持将使Ware博士能够扩大她的指导范围，包括新的努力，以提高她的学员的指导技能，以确保为未来一代以患者为导向的研究人员提供强有力的指导。此外，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，她将专注于如何释放无细胞血红蛋白，以及结合珠蛋白（无细胞血红蛋白的主要内源性清道夫）的遗传异质性，确定无细胞血红蛋白对肺移植后原发性移植物功能障碍（ARDS的一种形式）的影响。这些研究基于令人信服的初步数据，这些数据表明，术前血浆游离血红蛋白水平升高与肺移植受者原发性移植物功能障碍的发生密切相关，而触珠蛋白2：2基因型与严重脓毒症患者ARDS的发生相关。有三个具体目标。目的1将检验血浆游离血红蛋白水平与接受肺移植的患者发生PGD的风险相关的假设，以及这种关系在再灌注时被FiO 2改变的假设。目的2将检验受体结合珠蛋白2：2基因型与肺移植后PGD发生率较高相关的假设，以及这种关系被无细胞血红蛋白水平改变的假设。最后，目标3将通过量化脂质过氧化、内皮和肺上皮损伤和炎症的生物标志物，并检测其与术前和术后无细胞血红蛋白水平和触珠蛋白2：2基因型的相关性，确定无细胞血红蛋白增强原发性移植物功能障碍风险的机制。这些研究将导致更好地了解无细胞血红蛋白和结合珠蛋白基因型对原发性移植物功能障碍风险的影响，并可能导致改善供体选择标准和供体-受体匹配。此外，这些研究可能会导致新的治疗方法，用于预防和治疗原发性移植物功能障碍和非移植相关的ARDS。

 DESCRIPTION (provided by applicant): The overall goal of this renewal application for a Midcareer Investigator Award in Patient-Oriented Research is to enable Dr. Ware to continue to build and expand her research and mentoring programs in patient-oriented research in ARDS. This award will allow her to continue to devote significant protected time to her current mentees as well as to expand her mentoring to include new postdoctoral trainees and medical students. In addition, the support of this award will allow Dr. Ware to expand the reach of her mentoring to include new efforts to enhance the mentoring skills of her mentees in order to assure strong mentoring for future generation of patient-oriented researchers. In addition, Dr. Ware's program in patient-oriented research will be expanded in new and novel directions. Specifically, she will focus on how release of cell-free hemoglobin, and genetic heterogeneity in haptoglobin, the primary endogenous scavenger of cell-free hemoglobin, determine the effects of cell-free hemoglobin on primary graft dysfunction, a form of ARDS, after lung transplantation. These studies are based on compelling preliminary data demonstrating that elevated pre-operative plasma levels of cell-free hemoglobin are strongly associated with development of primary graft dysfunction in lung transplant recipients and that the haptoglobin 2:2 genotype is associated with development of ARDS in severe sepsis. There are three specific aims. Aim 1 will test the hypothesis that plasma cell-free hemoglobin levels are associated with risk of PGD in patients undergoing lung transplantation and that this relationship is modified by FiO2 at reperfusion. Aim 2 will test the hypothesis that recipient haptoglobin 2:2 genotype is associated with a higher incidence of PGD after lung transplantation and that this relationship is modified by cell-free hemoglobin levels. Finally, Aim 3 will determine the mechanism by which cell-free hemoglobin potentiates the risk of primary graft dysfunction by quantifying biomarkers of lipid peroxidation, endothelial and lung epithelial injury and inflammation and testing their associations with pre- and post-operative cell-free hemoglobin levels and haptoglobin 2:2 genotype. These studies will lead to a better understanding of the influence of cell-free hemoglobin and haptoglobin genotypes on risk of primary graft dysfunction and may lead to improved donor selection criteria and donor-recipient matching. In addition, these studies may lead to new treatments for prevention and treatment of both primary graft dysfunction and non-transplant associated ARDS.