Tissue Factor Mediated Fibrin Deposition in Acute Lung Injury

急性肺损伤中组织因子介导的纤维蛋白沉积

• 批准号: 7589907
• 负责人: Julie Anne Bastarache
• 金额: $ 12.57万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7589907
• 关键词: Academic Medical Centers; Acute; Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Alveolar; Animal Model; Animals; Attenuated; Cells; Coagulants; Coagulation Process; Data; Data Analyses; Deposition; Development; Disease; Distress; Environment; Epithelial; Experimental Designs; Fibrin; Floods; Foundations; Human; Inflammation; Inflammatory; Injury; Instruction; Knowledge; Laboratories; Lead; Link; Lung; Lung Inflammation; Manuscripts; Mechanical ventilation; Mediating; Modeling; Molecular; Mus; Pathogenesis; Pathway interactions; Peer Review; Peptide Hydrolases; Pharmaceutical Preparations; Play; Preparation; Process; Production; Research; Research Personnel; Role; Sepsis; Source; Stimulus; Structure of parenchyma of lung; Syndrome; Techniques; Testing; Therapeutic; Thrombin; Thromboplastin; Up-Regulation; Work; alveolar epithelium; career; chemokine; cytokine; design; driving force; experience; injured; lung development; lung injury; mortality; novel; novel strategies; novel therapeutics; research study; response; skills

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.

描述（由申请人提供）：该提案的目的是培养朱莉·巴斯塔赫（Julie Bastarache）博士的科学和专业发展，以便她成为独立的研究者。她目前正在Vanderbilt大学医学中心的肺研究中心发展研究生涯。在博士的指导下。 Bastarache博士Lorraine Ware和Timothy Blackwell将设计和执行实验，以提高她在急性肺损伤和急性呼吸遇险综合征（ALI/ARDS）病理生物学方面的知识和研究技能。通过实验室经验，正式课程和同行审查过程，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Bastarache博士从事肺部研究独立职业奠定基础。尽管在理解ALI/ARDS的基本致病机制方面取得了进展，但基本问题仍未得到解决，并且缺乏特定疾病的治疗方法。实验研究已经确定，肺泡内凝血酶的形成和纤维蛋白沉积是促凝液内肺泡环境的结果是有害的，但是，调节空体中纤维蛋白沉积的特定机制以及连接肺部炎症和凝聚的特定机制尚不清楚。我们的初步数据将肺泡上皮识别为组织因子（TF）的潜在来源，这是肺泡室中主要的促凝剂刺激。结果，我们形成了以下假设：响应促炎性刺激的局部生产空域中组织因子的局部生产会使炎症永久存在并导致肺损伤。肺中TF的抑制作用将减少纤维蛋白的形成，减少细胞因子的产生并限制肺损伤。为了检验该假设，我们将：1）确定调节急性损伤肺中TF活性，凝血酶形成和纤维蛋白沉积的因素。 2）定义衰减肺泡内TF活性对急性损伤肺部持续炎症和损伤的影响。 3）确定肺泡上皮中TF上调和激活的机制。这些研究的完成将提供有关ARDS发病机理的关键信息，这些信息可能导致新的治疗策略。相关性（请参阅说明）：急性呼吸窘迫综合征（ARDS）是一种常见疾病，死亡率很高，没有特定的药物治疗。新数据表明，涉及肺损伤的两种重要途径：炎症和凝结之间的关键联系。该建议将使用独特的动物模型来定义将这两种独立途径联系起来的特定机制，并有助于确定新疗法的关键目标。