PPAR gamma in pediatric sepsis and the inflammatory response in obesity

小儿脓毒症中的 PPAR γ 和肥胖症中的炎症反应

• 批准号: 8266438
• 负责人: Jennifer Melissa Kaplan
• 金额: $ 12.45万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8266438
• 关键词: 2,4-thiazolidinedione; Address; Adipocytes; Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotic Therapy; Basic Science; Blood specimen; Cessation of life; Child; Childhood; Chronic; Clinical; Critical Care; Critical Illness; Critically ill children; Data; Diet; Economic Burden; Educational Curriculum; Environment; Epidemiology; Event; Experimental Animal Model; Experimental Models; FDA approved; Fatty acid glycerol esters; Functional disorder; Funding; Immune response; Immune system; Immunology; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Investigation; Lead; Letters; Ligand Binding; Ligands; Ligation; Link; Lung; Medical center; Medicine; Mentors; Modeling; Molecular; Molecular Epidemiology; Morbidity - disease rate; Mus; Nuclear Receptors; Obesity; Organ; Organ failure; Outcome; PPAR gamma; Pathway interactions; Patients; Pediatric Hospitals; Pediatrics; Peripheral Blood Mononuclear Cell; Peroxisome Proliferator-Activated Receptors; Physiological; Post-Translational Protein Processing; Predisposition; Production; Public Health; Puncture procedure; Regulation; Research; Research Personnel; Research Project Grants; Research Training; Rodent; Role; Sepsis; Septic Shock; Signal Transduction; Testing; Thiazolidinediones; Thoracic aorta; Training; Treatment Efficacy; blood glucose regulation; cell injury; clinically relevant; design; experience; feeding; genetic manipulation; improved; in vivo; in vivo Model; insight; monocyte; mortality; novel; peripheral blood; professor; protein expression; public health relevance; receptor; research study; response; transcription factor; translational approach

DESCRIPTION (provided by applicant): This proposal represents a four-year curriculum and research plan that is designed to provide me with the means to transition to an independent investigator. I am an Assistant Professor in Pediatrics in the Division of Critical Care Medicine at Cincinnati Children's Hospital Medical Center with training in molecular epidemiology and sepsis-related basic science research. This application provides a proposed curriculum in epidemiology and immunology and a description of the proposed research project. Sepsis is a clinical entity that involves a massive systemic inflammatory response and can lead to multiple organ dysfunction and death. Systemic physiologic changes lead to endothelial injury, cellular damage and organ failure. The nuclear receptor, peroxisome proliferator-activated receptor-g (PPARg), is involved in the regulation of the inflammatory response in experimental models of sepsis but little is known about the effects in children. Our preliminary data suggest that PPARg is altered in experimental animal models and in critically ill children with sepsis. Furthermore we have demonstrated that diet is also an important factor of sepsis susceptibility in animal models. The central hypothesis of the application is that the PPARg pathway is altered in patients with sepsis and that diet further affects the inflammatory response to sepsis in a PPARg-dependent manner. This hypothesis will be tested by pursuing three specific aims: 1) Determine the alterations in the PPARg pathway in monocytes from children with sepsis; 2) Determine the therapeutic efficacy of PPARg ligands in the inflammatory response in ex vivo monocytes from children with septic shock; 3) Determine the role of PPARg in the increased susceptibility to sepsis in obesity. Under aim 1 we will utilize a clinical approach to investigate alterations in PPARg in peripheral blood monocytes from children with sepsis. Aim 2 will use a translational approach using ex vivo monocytes to investigate the therapeutic efficacy of PPARg ligands in altering the inflammatory response in sepsis. Aim 3 will use a basic science approach where in vivo and in vitro studies will be used to determine the role of PPARg in the increased susceptibility to sepsis in obesity. The proposed research is significant because it can lead to novel therapies for patients with sepsis, including the potential use of FDA-approved PPARg ligands, thiazolidinediones, which can augment the PPARg pathway. PUBLIC HEALTH RELEVANCE: The results of this investigation will provide useful information in developing new therapies to target the imbalance which occurs in children with sepsis. Furthermore, it will provide an understanding of the increased inflammatory state associated with obesity and of the increased susceptibility of obese patients to worse outcomes during critical illness.

描述（由申请人提供）：本提案代表了一个为期四年的课程和研究计划，旨在为我提供过渡到独立调查员的手段。我是辛辛那提儿童医院医学中心重症监护医学部的儿科助理教授，接受过分子流行病学和脓毒症相关基础科学研究的培训。此应用程序提供了一个流行病学和免疫学的拟议课程和拟议的研究项目的描述。脓毒症是一种涉及大量全身炎症反应并可导致多器官功能障碍和死亡的临床实体。全身生理变化导致内皮损伤、细胞损伤和器官衰竭。核受体，过氧化物酶体增殖物激活受体-g（PPARg），参与脓毒症实验模型中炎症反应的调节，但对儿童的影响知之甚少。我们的初步数据表明，PPARg在实验动物模型和败血症重症儿童中发生了改变。此外，我们已经证明，饮食也是一个重要的因素，脓毒症的易感性在动物模型。该申请的中心假设是，PPARg途径在脓毒症患者中发生改变，并且饮食以PPARg依赖性方式进一步影响对脓毒症的炎症反应。该假设将通过追求三个具体目标进行测试：1）确定脓毒症儿童单核细胞中PPARg途径的改变; 2）确定PPARg配体在脓毒症休克儿童离体单核细胞中炎症反应的治疗功效; 3）确定PPARg在肥胖症中脓毒症易感性增加中的作用。根据目标1，我们将利用临床方法研究脓毒症患儿外周血单核细胞中PPARg的变化。目的2将使用使用离体单核细胞的翻译方法来研究PPARg配体在改变脓毒症中的炎症反应中的治疗功效。目标3将使用基础科学方法，其中将使用体内和体外研究来确定PPARg在肥胖症败血症易感性增加中的作用。这项研究意义重大，因为它可以为脓毒症患者带来新的治疗方法，包括FDA批准的PPARg配体噻唑烷二酮的潜在用途，这可以增强PPARg通路。 公共卫生相关性：这项研究的结果将为开发新的治疗方法提供有用的信息，以针对脓毒症儿童中发生的不平衡。此外，它将提供与肥胖相关的炎症状态增加和肥胖患者在危重病期间对更差结果的易感性增加的理解。