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）：该职业发展奖的目的是增强对急性肺损伤（ALI）发病机理的理解，以促进开发新的有效疗法。阿里是一种常见的致命形式的呼吸衰竭，每年发生在200,000人中，多达25％的机械通风患者发生。目前没有有效的ALI医疗疗法，死亡率仍为近40％。慢性合并症状况改变了患ALI的风险，糖尿病（DM）是唯一发现降低败血性休克患者ALI发生率的疾病。这种意外的观察是检查ALI发病机理的基础，以了解减轻这种病态急性疾病风险的疾病改良途径。 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，在健康健康的糖尿病患者中，PPARG活性是AM激活的关键调节剂。并且AM功能在败血症中降低，这是ALI的最常见原因。在这种情况下，可以假设AM中的相对PPARG激活应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开发之间的关联对于研究至关重要。此外，PPARG激活代表了一个有吸引力的治疗靶标，不仅在糖尿病患者中，而且还可以降低急性肺损伤的发生率或严重性，而且还可以降低具有脓毒症或其他急性应激的非糖尿病患者。在这种背景下，我们假设与健康对照组相比，其他健康的糖尿病患者的AM PPARG活性将增加，并且AM PPARG活性降低和严重败血症的吞噬功能与ALI风险增加有关。此外，我们假设在体外使用PPARG-LIGAND的AM治疗将增加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。我们的假设将在旨在的特定目的中进行检验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分化和吞噬功能的预测值； 3）确定体外PPARG-配体暴露对从对照，糖尿病和化粪池患者中分离出的AM的表型和功能的影响。总体目标是确定糖尿病与ALI发病率之间的关联是否转化为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，我们将进行其他健康糖尿病患者，严重败血症和健康对照的受试者的研究。合格的受试者将进行支气管镜检查，并进行支气管肺泡灌洗，以分离AM并进行测量测量PPARG活性，AM分化标记（M1/M2标记）和AM吞噬功能的测定法。在AIM 3测试中，将重复这些研究，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是肺中急性炎症反应的关键调节成分，并有效地抑制了ALI动物模型的炎症和损伤，因此我们必须研究该受体在人类肺部疾病中的致病性和潜在治疗作用。拟议的研究将在有经验的导师的指导下进行，该导师在进行临床研究方面具有专业知识，并在进行基础研究方面具有专业知识；由职业发展委员会的补充，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能够建立在以前的研究中创造的基础上，并继续朝着成为一个独立的临床研究者的目标，最终是成为ALI发病机理专家的最终目标。这将通过完成MSCR计划和免疫学课程，与我的导师的互动以及完善的咨询委员会以及Emory环境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的NIH资金（此类R01奖项）提供直接途径，这将使我能够成功地扩展我的研究重点并扩大我们对ALI病理生理学的理解。