PPAR?? and Alveolar Macrophage Phenotype in Acute Lung Injury

过氧化物酶体受体??

• 批准号: 8500431
• 负责人: ANNETTE M. ESPER
• 金额: $ 15.26万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-06 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500431
• 关键词: 2,4-thiazolidinedione; Abdomen; Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Advisory Committees; Affect; Age; Alveolar; Alveolar Macrophages; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Award; Basic Science; Biological; Biological Assay; Bronchoscopy with Bronchoalveolar Lavage; Capillary Permeability; Chronic; Clinical Investigator; Clinical Research; Collaborations; Critical Illness; Data; Development; Diabetes Mellitus; Disease; Environment; Foundations; Functional disorder; Funding; Future; Goals; HIV; Human; Immunology; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory Response; Injury; K-Series Research Career Programs; Lead; Life; Ligands; Lung; Lung diseases; Macrophage Activation; Malignant Neoplasms; Measures; Medical; Mentored Patient-Oriented Research Career Development Award; Mentors; Morbidity - disease rate; Oxidative Stress; Oxidative Stress Pathway; PPAR gamma; Pathogenesis; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Phagocytosis; Phenotype; Pneumonia; Populations at Risk; Predictive Value; Predisposing Factor; Relative (related person); Reporting; Research; Resolution; Respiratory Failure; Risk; Role; Sepsis; Septic Shock; Severities; Signal Pathway; Testing; Therapeutic; Therapeutic Effect; Thiazolidinediones; Training; Translating; United States National Institutes of Health; activity marker; acute stress; career development; chronic liver disease; cytokine; design; diabetic; effective therapy; experience; falls; high risk; immune function; improved; lung injury; mortality; non-diabetic; prevent; programs; receptor; response; septic; skills; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): The objective of this Career Development Award is to enhance understanding of acute lung injury (ALI) pathogenesis in order to facilitate development of new effective therapies. ALI is a common and lethal form of respiratory failure, occurring in 200,000 people each year and in as many as 25% of mechanically ventilated patients. There are presently no effective medical therapies for ALI, and mortality remains at nearly 40%. Chronic co-morbid conditions alter the risk for developing ALI, and diabetes mellitus (DM) is the only identified condition shown to decrease the incidence of ALI in patients with septic shock. This unexpected observation serves as the foundation for examining ALI pathogenesis to understand disease-modifying pathways to mitigate the risk for such a morbid acute illness. PPARg activity influences AM host immune functions including phagocytosis, and our preliminary data suggest that PPARg activity, a key regulator of AM activation, is increased in otherwise healthy diabetics; and that AM function is decreased in sepsis, the most common cause of ALI. In this context, one could postulate that the relative PPARg activation in the AM should correlate with the risk of ALI in diabetics as well as in non-diabetics. Therefore, the association between AM function and ALI development is of importance to investigate. In addition, PPARg activation represents an attractive therapeutic target that could decrease the incidence or severity of acute lung injury not only in diabetics, but also in non-diabetics with sepsis or other acute stresses. With this background, we hypothesize that otherwise healthy diabetics will have increased AM PPARg activity when compared to healthy controls and that decreased AM PPARg activity and phagocytic function in severe sepsis are independently associated with increased risk of ALI. Furthermore, we hypothesize that treatment of AMs with a PPARg-ligand in vitro will increase PPARg activity, thereby increasing expression of the alternative activation (M2) anti-inflammatory phenotype and improving phagocytosis. Our hypothesis will be tested in Specific Aims designed to 1) determine the effect of DM on alveolar macrophage (AM) PPARg activity, phenotype and phagocytic function; 2) establish the predictive value of AM PPAR3 activity, AM M2 differentiation and phagocytic function for the development of ALI; and 3) determine the effect of PPARg-ligand exposure in vitro on the phenotype and function of AMs isolated from control, diabetic and septic patients. The overall objective is to determine if the association between diabetes and decreased incidence of ALI translates to an association between increase PPARg activity and decreased risk of ALI. To test our hypothesis, we will conduct studies in otherwise healthy diabetics, subjects with severe sepsis and healthy controls. Eligible subjects will undergo bronchoscopy with bronchoalveolar lavage to isolate AMs and perform assays measuring PPARg activity, markers of AM differentiation (M1/M2 markers) and AM phagocytic function. These studies will be repeated, in Aim 3 testing exposure of AMs to PPARg ligand and determining its effect on AM differentiation and phagocytic function. The proposed studies will evaluate the impact of PPARg activity on development of ALI and will determine the role of PPARg in regulating AMs response to pulmonary inflammation. Since PPARg is a key regulatory component of acute inflammatory responses in the lung, and effectively dampens inflammation and injury in animal models of ALI, it is imperative that we investigate the pathogenetic and potential therapeutic role of this receptor in human lung disease. The proposed studies will be carried out under the guidance of an experienced mentor who has expertise in conducting clinical research, and a co-mentor with expertise in conducting basic research; supplemented by a career development committee and collaborations with a multi-disciplinary scientific team. The support provided by the K23 Career Development Award will allow me to build upon the foundation I have created with my previous studies, and continue towards my goal of becoming an independent clinical investigator with the ultimate goal of becoming an expert in ALI pathogenesis. This will be accomplished by receiving didactic training through completion of the MSCR program and courses in immunology, interactions with my mentor and a well-established advisory committee, and the Emory environment, all of which will further refine and develop my investigational and analytical skills. The training opportunity provided by the K23 program will provide a direct path for obtaining future NIH funding, such R01 awards, which will allow me to successfully extend my research focus and broaden our understanding of the pathophysiology of ALI.

简介(申请人提供)：此职业发展奖的目的是增进对急性肺损伤(ALI)发病机制的了解，以促进新的有效治疗方法的发展。ALI是一种常见的致命呼吸衰竭形式，每年发生在20万人和多达25%的机械通气患者中。目前尚无有效的治疗ALI的药物，死亡率仍保持在近40%。慢性合并症改变了发生ALI的风险，而糖尿病(DM)是唯一能降低感染性休克患者ALI发生率的疾病。这一意想不到的观察为研究ALI发病机制奠定了基础，以了解降低这种病态急性疾病风险的疾病修改途径。PPARG活性影响AM宿主的免疫功能，包括吞噬功能，我们的初步数据表明，在其他健康的糖尿病患者中，AM激活的关键调节因子PPARg活性增加；而在脓毒症中，AM功能降低，这是ALI最常见的原因。在这种情况下，人们可以假设AM中PPARg的相对激活应该与糖尿病患者和非糖尿病患者的ALI风险相关。因此，AM功能与ALI发生发展之间的关系值得深入研究。此外，PPARg活化是一个有吸引力的治疗靶点，不仅可以降低糖尿病患者急性肺损伤的发生率或严重程度，而且可以降低非糖尿病患者合并脓毒症或其他急性应激反应的发生率或严重程度。在此背景下，我们假设，与健康对照组相比，其他健康的糖尿病患者AM PPARg活性增加，严重脓毒症患者AM PPARg活性和吞噬功能降低与ALI风险增加独立相关。此外，我们假设在体外用PPARg配体处理AM会增加PPARg的活性，从而增加交替激活(M2)抗炎表型的表达，并改善吞噬功能。我们的假设将在特定的目标下进行检验，目的是1)确定DM对肺泡巨噬细胞(AM)PPARg活性、表型和吞噬功能的影响；2)建立AM PPAR3活性、AM M2分化和吞噬功能对ALI发生的预测价值；3)确定体外暴露PPARg配体对对照组、糖尿病和脓毒症患者分离的AM表型和功能的影响。总体目标是确定糖尿病和ALI发病率降低之间的关联是否转化为PPARg活性增加和ALI风险降低之间的关联。为了验证我们的假设，我们将对其他健康的糖尿病患者、患有严重脓毒症的受试者和健康对照组进行研究。符合条件的受试者将接受支气管镜检查和支气管肺泡灌洗分离AM，并进行PPARg活性、AM分化标志物(M1/M2标志物)和AM吞噬功能的检测。这些研究将重复进行，目的3测试AM对PPARg配体的暴露，并确定其对AM分化和吞噬功能的影响。这些研究将评估PPARg活性对ALI发展的影响，并将确定PPARg在调节AM对肺部炎症反应中的作用。由于PPARg是肺部急性炎症反应的关键调节成分，并有效地抑制ALI动物模型的炎症和损伤，因此我们迫切需要研究该受体在人类肺部疾病中的致病作用和潜在的治疗作用。拟议的研究将在一名在临床研究方面有专长的经验丰富的导师和一名在基础研究方面有专长的共同导师的指导下进行，并辅之以一个职业发展委员会和一个多学科科学团队的合作。K23职业发展奖提供的支持将使我能够在我之前的研究创造的基础上再接再厉，继续朝着成为一名独立的临床研究员的目标前进，最终目标是成为ALI发病机制的专家。这将通过完成MSCR计划和免疫学课程的授课培训、与我的导师和成熟的咨询委员会的互动以及埃默里环境来实现，所有这些都将进一步完善和发展我的调查和分析技能。K23计划提供的培训机会将为未来获得NIH资金提供直接途径，如R01奖项，这将使我能够成功地扩大我的研究重点，并拓宽我们对ALI病理生理学的理解。