INNATE IMMUNE REGULATION OF PRIMARY GRAFT DYSFUNCTION

原发性移植物功能障碍的先天免疫调节

• 批准号: 8092287
• 负责人: HOWARD J HUANG
• 金额: $ 12.03万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8092287
• 关键词: Acute; Acute Lung Injury; Adaptor Signaling Protein; Allografting; Antibodies; Bronchiolitis Obliterans; Bronchoalveolar Lavage Fluid; Cessation of life; Data; Development Plans; Experimental Models; Functional disorder; Goals; HMGB1 Protein; Health Care Costs; Hour; Human; Hyaluronic Acid; Immune; Immunobiology; Immunologics; Inflammatory; Injury; Ischemia; Isogenic transplantation; K-Series Research Career Programs; Laboratories; Lung; Lung Transplantation; Mediating; Mediator of activation protein; Mentors; Modeling; Molecular; Molecular Weight; Morbidity - disease rate; Mus; Organ; Organ Transplantation; Outcome; Patients; Pattern; Peptides; Physiological; Play; Population; Production; Pulmonary Edema; Receptor Signaling; Regulation; Relative (related person); Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Risk; Risk Factors; Role; Serum; Severities; Signal Pathway; Signal Transduction; Small Interfering RNA; Solid; Sterility; Syndrome; Testing; Therapeutic; Tissues; Toll-Like Receptor 2; Toll-like receptors; Training; Training Support; Translating; Transplant Recipients; Transplantation; career development; cytokine; functional outcomes; graft failure; granulocyte; human data; improved; insight; lung allograft; lung ischemia; mortality; mouse model; novel; novel therapeutic intervention; protein expression; receptor function; research study; therapeutic target; toll-like receptor 4; translational study

DESCRIPTION (provided by applicant): PROJECT ABSTRACT Acute lung injury within 72 hours of lung transplantation, termed Primary Graft Dysfunction (PGD), is a major cause of early post-transplant morbidity and mortality. PGD results in increased healthcare costs and poor functional outcomes for lung allograft recipients. Importantly, PGD is also a risk factor for developing Bronchiolitis Obliterans Syndrome, the main cause of late graft failure and death in this population. Therapeutic strategies aimed at ameliorating PGD may extend post-transplant allograft and patient survival. However, the pathophysiologic mechanisms regulating PGD remain poorly understood, and additional experimental studies are needed to identify novel approaches for therapeutic modulation. Ischemia-reperfusion injury is a major determinant of PGD, and is associated with activation of pro-inflammatory signaling pathways initiated by toll- like receptors. Toll-like receptors 2 and 4 recognize damage-associated molecular patterns released by sterile tissue injury, which have been reported in serum and bronchoalveolar lavage fluid of human lung transplant recipients. Accordingly, we hypothesize that lung ischemia-reperfusion injury releases endogenous damage-associated molecular patterns, which promote PGD through activation of toll-like receptors. Using a novel mouse orthotopic lung transplant model that replicates the physiologic, histopathologic and immunologic features of human PGD, we will test this hypothesis with two specific aims: 1) Characterize the role of toll-like receptors 2 and 4 in ischemia-reperfusion-induced lung graft injury, and 2) Characterize the role of damage-associated molecular patterns in ischemia-reperfusion-induced lung graft injury. Collectively, the studies proposed here are aimed at generating new insight into the pathophysiology of PGD and identifying potential pharmacologic targeting strategies for treating PGD in the context of a mentored career development plan. My long-term goal is to become an academic pulmonologist with a research focus in transplant immunobiology. The mentoring, training and support facilitated by this K08 career development award will enable me to acquire the training and expertise necessary for translating novel findings in experimental models to therapeutic strategies for treating lung allograft injury and rejection in humans. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Primary graft dysfunction is the major cause of early morbidity and mortality following lung transplantation, and has been associated with an increased risk for developing bronchiolitis obliterans syndrome and late graft failure. This project will investigate the role of innate immune signaling pathways in regulating primary graft dysfunction using a novel mouse model. We aim to identify potential pharmacologic targeting strategies for treating primary graft dysfunction and improving post-lung transplant outcomes. )

描述（由申请人提供）：项目抽象的急性肺损伤在肺移植后72小时内称为原发性移植功能障碍（PGD），是移植后早期发病率和死亡率的主要原因。 PGD​​导致肺同种异体接受者的医疗保健成本增加和功能不良。重要的是，PGD也是发展支气管炎的危险因素，这是该人群晚期移植失败和死亡的主要原因。旨在改善PGD的治疗策略可能会延长移植后同种异体移植物和患者生存。然而，调节PGD的病理生理机制仍然很少了解，需要进行其他实验研究来识别治疗调节的新方法。缺血 - 再灌注损伤是PGD的主要决定因素，并且与Toll-High-Hodyor引发的促炎信号传导途径的激活有关。 Toll样受体2和4识别与无菌组织损伤释放的损伤相关的分子模式，这些分子模式已在人类肺移植受者的血清和支气管肺泡灌洗液中报道。因此，我们假设肺部缺血再灌注损伤释放了内源性损伤相关的分子模式，从而通过激活Toll样受体来促进PGD。使用新型的小鼠原位肺移植模型，该模型复制人类PGD的生理，组织病理学和免疫学特征，我们将以两个特定的目的检验该假设：1）表征性质诱导的肺部损伤的作用，表征了Toll-like受体2和4的作用。缺血再灌注诱导的肺移植损伤。总的来说，此处提出的研究旨在为PGD的病理生理生理新见解，并确定在指导的职业发展计划中治疗PGD的潜在药理靶向策略。我的长期目标是成为一名学术肺科医生，研究重点是移植免疫生物学。这项K08职业发展奖为促进的指导，培训和支持将使我能够获得将实验模型中新颖发现的新颖发现的培训和专业知识转化为治疗人类肺同种异体损伤和拒绝的治疗策略。 公共卫生相关性：项目叙事主要移植功能障碍是肺移植后早期发病率和死亡率的主要原因，并且与患有闭塞性细支气管炎综合征和晚期移植失败的风险增加有关。该项目将研究先天免疫信号通路在使用新型小鼠模型调节原发性移植功能障碍中的作用。我们旨在确定潜在的药理靶向策略，以治疗原发性移植功能障碍并改善肺部移植后预后。 ）