PPAR?? and Alveolar Macrophage Phenotype in Acute Lung Injury

过氧化物酶体受体??

• 批准号: 8298159
• 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/8298159
• 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.

描述（由申请人提供）：该职业发展奖的目的是增强对急性肺损伤（ALI）发病机制的了解，以促进新的有效疗法的开发。 ALI 是一种常见且致命的呼吸衰竭，每年有 200,000 人发生这种情况，其中多达 25% 的机械通气患者发生这种情况。目前ALI尚无有效的药物治疗方法，死亡率仍接近40%。慢性共病会改变发生 ALI 的风险，而糖尿病 (DM) 是唯一已确定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 发病机制奠定了基础，以了解疾病缓解途径，从而减轻这种急性病的风险。 PPARg 活性影响 AM 宿主免疫功能，包括吞噬作用，我们的初步数据表明，PPARg 活性（AM 激活的关键调节因子）在其他健康的糖尿病患者中增加； AM 功能在脓毒症（ALI 的最常见原因）中下降。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以及非糖尿病患者的 ALI 风险相关。因此，研究 AM 功能与 ALI 发展之间的关联具有重要意义。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的发生率或严重程度，还可以降低患有脓毒症或其他急性应激的非糖尿病患者的急性肺损伤的发生率或严重程度。在此背景下，我们假设与健康对照相比，健康的糖尿病患者 AM PPARg 活性增加，并且严重脓毒症中 AM PPARg 活性和吞噬功能的降低与 ALI 风险增加独立相关。此外，我们假设体外用 PPARg 配体处理 AM 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。我们的假设将在特定目标中进行检验，旨在 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 PPARg 配体暴露对从对照、糖尿病和脓毒症患者中分离出的 AM 的表型和功能的影响。总体目标是确定糖尿病与 ALI 发病率降低之间的关联是否可以转化为 PPARg 活性增加与 ALI 风险降低之间的关联。为了检验我们的假设，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者进行研究。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，并进行测量 PPARg 活性、AM 分化标志物（M1/M2 标志物）和 AM 吞噬功能的测定。这些研究将在目标 3 中重复进行，测试 AM 与 PPARg 配体的接触，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，并确定 PPARg 在调节 AMs 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，并能有效抑制 ALI 动物模型中的炎症和损伤，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治疗作用。拟议的研究将在一位具有临床研究专业知识的经验丰富的导师和一位具有进行基础研究专业知识的共同导师的指导下进行；辅以职业发展委员会以及与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之前的研究基础上继续努力，继续实现成为一名独立临床研究者的目标，最终目标是成为 ALI 发病机制方面的专家。这将通过完成 MSCR 计划和免疫学课程、与我的导师和完善的咨询委员会以及埃默里环境的互动来接受教学培训来实现，所有这些都将进一步完善和发展我的研究和分析技能。 K23 计划提供的培训机会将为获得未来 NIH 资助（例如 R01 奖项）提供直接途径，这将使我能够成功扩展我的研究重点并拓宽我们对 ALI 病理生理学的理解。