PPAR?? and Alveolar Macrophage Phenotype in Acute Lung Injury

过氧化物酶体受体??

• 批准号: 8190250
• 负责人: ANNETTE M. ESPER
• 金额: $ 15.14万
• 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/8190250
• 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; Liver diseases; 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; 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.

描述（由申请人提供）：本职业发展奖的目的是加强对急性肺损伤（ALI）发病机制的了解，以促进新的有效治疗方法的发展。ALI是一种常见且致命的呼吸衰竭形式，每年有20万人发生，在机械通气患者中占25%。目前还没有有效的药物治疗ALI，死亡率保持在近40%。慢性合并症可改变发生ALI的风险，而糖尿病（DM）是唯一确定的可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结果为研究ALI的发病机制提供了基础，从而了解疾病修饰途径，以减轻这种病态急性疾病的风险。PPARg活性影响AM宿主免疫功能，包括吞噬，我们的初步数据表明，PPARg活性是AM激活的关键调节因子，在其他健康的糖尿病患者中增加；在脓毒症中AM功能下降，这是ALI最常见的原因。在这种情况下，可以假设AM中相对的PPARg激活应该与糖尿病患者和非糖尿病患者发生ALI的风险相关。因此，研究AM功能与ALI发展之间的关系非常重要。此外，PPARg激活是一个有吸引力的治疗靶点，不仅可以降低糖尿病患者的急性肺损伤发生率或严重程度，也可以降低非糖尿病患者脓毒症或其他急性应激的急性肺损伤。在此背景下，我们假设与健康对照相比，健康糖尿病患者AM PPARg活性增加，严重脓毒症患者AM PPARg活性和吞噬功能下降与ALI风险增加独立相关。此外，我们假设体外用PPARg配体处理AMs会增加PPARg活性，从而增加替代激活（M2）抗炎表型的表达，并改善吞噬作用。我们的假设将在Specific Aims中得到验证，目的是：1)确定DM对肺泡巨噬细胞（AM） ppar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发展的预测价值；3)确定体外暴露ppar配体对对照、糖尿病和脓毒症患者分离的AMs表型和功能的影响。总体目标是确定糖尿病和降低ALI发病率之间的关联是否转化为ppar活性增加和降低ALI风险之间的关联。为了验证我们的假设，我们将在健康的糖尿病患者、严重败血症患者和健康对照者中进行研究。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以分离AM，并进行PPARg活性、AM分化标记物（M1/M2标记物）和AM吞噬功能测定。这些研究将在Aim 3中重复进行，测试AM暴露于PPARg配体并确定其对AM分化和吞噬功能的影响。拟议的研究将评估PPARg活性对ALI发展的影响，并将确定PPARg在调节AMs对肺部炎症反应中的作用。由于PPARg是肺急性炎症反应的关键调控成分，并且在ALI动物模型中有效地抑制炎症和损伤，因此我们有必要研究该受体在人类肺部疾病中的发病机制和潜在的治疗作用。拟议的研究将在一名具有临床研究专长的经验丰富的导师和一名具有基础研究专长的联合导师的指导下进行；辅以职业发展委员会，并与多学科科学团队合作。K23职业发展奖提供的支持将使我在之前的研究基础上继续前进，并继续朝着成为一名独立临床研究者的目标前进，最终目标是成为ALI发病机制方面的专家。这将通过完成MSCR项目和免疫学课程，与我的导师和完善的咨询委员会以及埃默里大学的环境进行互动，接受教学培训来完成，所有这些都将进一步完善和发展我的研究和分析技能。K23项目提供的培训机会将为今后获得NIH的资助，如R01奖，提供一个直接的途径，这将使我成功地扩展我的研究重点，拓宽我们对ALI病理生理学的理解。