Adenosine 2A Receptor Signaling in Lung Transplant Injury and Rejection

肺移植损伤和排斥反应中的腺苷 2A 受体信号转导

• 批准号: 7752599
• 负责人: Christine L Lau
• 金额: $ 12.88万
• 依托单位: UNIVERSITY OF VIRGINIA
• 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/7752599
• 关键词: Abbreviations; Acute; Address; Adenosine; Adenosine A2A Receptor; Advisory Committees; Agonist; Alloantigen; Allografting; Alteplase; Alveolar; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Antigen-Presenting Cells; Attenuated; Bronchiolitis Obliterans; Bronchoalveolar Lavage; Calcineurin inhibitor; Cells; Chronic; Cyclosporine; Development; Diffuse; Disease; Etiology; Extravasation; Functional disorder; Genes; Glossary; Graft Rejection; Grant; Growth; Hematoxylin and Eosin Staining Method; Hypoxemia; Immune response; Immunosuppression; In Vitro; Inflammatory; Injury; Instruction; Ischemia; Kinetics; Knock-out; Knockout Mice; Lung; Lymphocyte; Lymphocyte antigen; Mediating; Mentors; Mixed Lymphocyte Culture Test; Modeling; Morbidity - disease rate; Mouse Strains; Mus; Natural Killer Cells; Operative Surgical Procedures; Pathogenesis; Phosphate Buffer; Plasminogen Activator Inhibitor 1; Polymerase Chain Reaction; Prevention; Principal Investigator; Process; Receptor Signaling; Regimen; Regulatory T-Lymphocyte; Reperfusion Injury; Reperfusion Therapy; Research Personnel; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Role; Saline; Signal Transduction; Sirolimus; T cell anergy; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Trachea; Training Programs; Transplant Recipients; Transplantation; Universities; Up-Regulation; Virginia; airway epithelium; allograft rejection; anergy; in vivo; in vivo Model; insight; killer T cell; lung allograft; lung ischemia; mortality; neutrophil; novel; nuclear factors of activated T-cells; peripheral tolerance; pre-clinical; prevent; protective effect; receptor; repaired; research study; response; skills; treatment strategy

DESCRIPTION (provided by applicant): The pathogenesis of lung ischemia reperfusion injury (IRI) has historically been characterized by the recruitment and extravasation of neutrophils. However, more recent studies have suggested a role for natural killer T-cells (NKT) in the pathogenesis of this injury. Agonists of the anti-inflammatory Gs-coupled adenosine A2A receptor (A2AR) have been shown to inhibit the activity of most inflammatory cells, and extensive preclinical evidence exists for their use in prevention of acute ischemia reperfusion. Importantly, IRI is a significant risk factor for the development of chronic allograft rejection, bronchiolitis obliterans (BO). Evidence supports alloimmune-dependent and alloimmune-independent factors in the etiology BO. More recently activation of A2ARs on lymphocytes and antigen presenting cells have been shown to attenuate the alloimmune response. Additionally A2AR stimulation and upregulation on lymphocytes promotes peripheral tolerance by inducing T-cell anergy. Currently little is known about the role of A2AR agonists in lung transplant rejection. Our overall hypothesis is that A2AR signaling is critical in modulating the innate and adaptive immune responses relevant to the pathogenesis of BO. Aim 1: Will determine, using an in-vivo lung IRI model, if A2AR signaling specifically on NKT cells confers protection from lung IRI. Aim 2: Will determine, using a non-revascularized heterotopic tracheal model and genetically modified mice strains, the importance and cellular mechanisms of A2AR signaling in the pathogenesis of BO. Aim 3: Will determine if A2AR signaling can be used to promote the development of a tolerant state. Also addressed will be ways to effectively introduce A2AR agonists with standard immunosuppression regimens. This grant encompasses a training program for the PI which includes coursework plus frequent interactions with mentors and advisors. With the guidance of the candidate's advisory committee and the institutional support provided by the University of Virginia's Department of Surgery, the candidate will development the skills required to evolve into an independent investigator. RELEVANCE (See instructions): BO remains the major hurdle to long-term survival in lung transplant recipients. There currently are no uniformly consistent strategies to prevent/treat BO. IRI is a significant risk factor for BO. Given the anti- inflammatory and immunomodulating effects of A2ARs, strategies utilizing A2AR agonists may be uniquely suited to prevent both the alloimmune-independent and alloimmune-dependent factors involved in BO.

描述（由申请人提供）：肺缺血再灌注损伤（IRI）的发病机制历来以中性粒细胞的募集和外渗为特征。然而，最近的研究表明自然杀伤 T 细胞 (NKT) 在这种损伤的发病机制中发挥着作用。抗炎 Gs 偶联腺苷 A2A 受体 (A2AR) 激动剂已被证明可以抑制大多数炎症细胞的活性，并且存在大量临床前证据表明它们可用于预防急性缺血再灌注。重要的是，IRI 是发生慢性同种异体移植排斥、闭塞性细支气管炎 (BO) 的重要危险因素。有证据支持 BO 病因中存在同种免疫依赖性和同种免疫非依赖性因素。最近，淋巴细胞和抗原呈递细胞上的 A2AR 激活已被证明可以减弱同种免疫反应。此外，A2AR 对淋巴细胞的刺激和上调可通过诱导 T 细胞无反应性来促进外周耐受性。目前对于 A2AR 激动剂在肺移植排斥反应中的作用知之甚少。我们的总体假设是 A2AR 信号传导对于调节与 BO 发病机制相关的先天性和适应性免疫反应至关重要。目标 1：将使用体内肺 IRI 模型确定 NKT 细胞上特异的 A2AR 信号传导是否能提供针对肺 IRI 的保护。目标 2：将使用非血运重建异位气管模型和转基因小鼠品系确定 A2AR 信号传导在 BO 发病机制中的重要性和细胞机制。目标 3：确定 A2AR 信号传导是否可用于促进耐受状态的发展。还讨论了通过标准免疫抑制方案有效引入 A2AR 激动剂的方法。这笔赠款包括 PI 的培训计划，其中包括课程作业以及与导师和顾问的频繁互动。在候选人咨询委员会的指导和弗吉尼亚大学外科系提供的机构支持下，候选人将发展成为独立调查员所需的技能。相关性（参见说明）：BO 仍然是肺移植受者长期生存的主要障碍。目前尚无统一一致的预防/治疗 BO 的策略。 IRI 是 BO 的一个重要危险因素。鉴于 A2AR 的抗炎和免疫调节作用，利用 A2AR 激动剂的策略可能特别适合预防 BO 中涉及的同种免疫非依赖性和同种免疫依赖性因子。