Tissue Factor Mediated Fibrin Deposition in Acute Lung Injury

描述(申请人提供)：本建议的目的是为了培养朱莉·巴斯塔拉奇博士的科学和专业发展，使她能够成为一名独立的调查人员。她目前在范德比尔特大学医学中心的肺脏研究中心发展她的研究事业。在Lorraine Ware博士和Timothy Blackwell博士的指导下，Bastarache博士将设计和进行实验，以增强她在急性肺损伤和急性呼吸窘迫综合征(ALI/ARDS)病理生物学方面的知识和研究技能。通过实验室经验、正式课程和同行评审过程，她将获得实验设计和执行、实验室技术、数据分析和手稿准备方面的专业知识。这些技能将为巴斯塔拉奇博士在肺部研究领域寻求独立的职业生涯奠定基础。尽管在了解ALI/ARDS的基本发病机制方面取得了进展，但基本的问题仍然没有得到回答，也缺乏针对疾病的特异性治疗。实验研究已经证实，促凝剂肺泡内环境导致的肺泡内凝血酶形成和纤维蛋白沉积是有害的，然而，调节空气中纤维蛋白沉积并将肺部炎症和凝血联系起来的具体机制尚不清楚。我们的初步数据确定肺泡上皮是组织因子(TF)的潜在来源，组织因子是肺泡室中主要的促凝血剂刺激。因此，我们形成了以下假说：在空气中局部产生组织因子，以响应促炎刺激，使炎症持续存在，并导致肺损伤。抑制肺组织中的转铁蛋白将减少纤维蛋白的形成，减少细胞因子的产生，限制肺损伤。为了验证这一假设，我们将：1)确定调节急性损伤肺组织中TF活性、凝血酶形成和纤维蛋白沉积的因素。2)明确减轻肺泡内转铁蛋白活性对急性损伤肺持续炎症和损伤的影响。3)确定Tf在肺泡上皮细胞中上调和激活的机制。这些研究的完成将提供有关ARDS发病机制的关键信息，可能导致新的治疗策略。相关性(见说明)：急性呼吸窘迫综合征(ARDS)是一种常见疾病，死亡率很高，没有特殊的药物治疗。新的数据表明，参与肺损伤的两条重要途径之间存在关键联系：炎症和凝血。这项提议将使用独特的动物模型来定义连接这两个独立途径的具体机制，并将有助于确定新疗法的关键靶点。

DESCRIPTION (provided by applicant): The purpose of this proposal is to cultivate the scientific and professional development of Dr. Julie Bastarache so that she may become an independent investigator. She is currently developing her research career in the Center for Lung Research at Vanderbilt University Medical Center. Under the guidance of Drs. Lorraine Ware and Timothy Blackwell, Dr. Bastarache will design and perform experiments that will enhance her knowledge and research skills in the pathobiology of acute lung injury and acute respiratory distress syndrome (ALI/ARDS). Through laboratory experience, formal coursework, and the peer review process she will gain expertise in experimental design and execution, laboratory techniques, data analysis, and manuscript preparation. These skills will provide the foundation for Dr. Bastarache to pursue an independent career in lung research. Despite progress in understanding the basic pathogenic mechanisms of ALI/ARDS, fundamental questions remain unanswered and disease specific treatments are lacking. Experimental studies have established that intra-alveolar thrombin formation and fibrin deposition as a consequence of a pro-coagulant intra-alveolar environment are detrimental however, the specific mechanisms that regulate fibrin deposition in the airspaces and link lung inflammation and coagulation are unknown. Our preliminary data identifies the alveolar epithelium as a potential source of tissue factor (TF), the major pro-coagulant stimulus in the alveolar compartment. As a result we have formed the following hypothesis: Local production of tissue factor in the airspace in response to pro-inflammatory stimuli perpetuates inflammation and leads to lung injury. Inhibition of TF in the lungs will reduce fibrin formation, decrease cytokine production and limit lung injury. To test this hypothesis we will:1) determine the factors that regulate TF activity, thrombin formation, and fibrin deposition in the acutely injured lung. 2) define the impact of attenuating intra-alveolar TF activity on ongoing inflammation and injury in the acutely injured lung. 3) determine the mechanisms of TF upregulation and activation in the alveolar epithelium. Completion of these studies will provide critical information about the pathogenesis of ARDS that could lead to novel therapeutic strategies. RELEVANCE (See instructions): The Acute Respiratory Distress Syndrome (ARDS) is a common disorder with a high mortality rate with no specific drug treatments. New data suggests critical links between two important pathways involved in lung injury: inflammation and coagulation. This proposal will use unique animal models to define the specific mechanisms that link these two independent pathways and will help to identify key targets for new therapies.