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

基本信息

批准号：
8472498
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
项目类别：
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/8472498
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 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

项目摘要

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.

描述（由申请人提供）：该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研究者的方法。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方面的培训。该应用程序提供了流行病学和免疫学的拟议课程以及拟议研究项目的描述。脓毒症是一种涉及大量全身炎症反应的临床疾病，可导致多器官功能障碍和死亡。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，但对其对儿童的影响知之甚少。我们的初步数据表明，PPARg 在实验动物模型和患有脓毒症的危重儿童中发生了改变。此外，我们已经证明，饮食也是动物模型中脓毒症易感性的重要因素。该申请的中心假设是脓毒症患者的 PPARg 通路发生改变，并且饮食以 PPARg 依赖性方式进一步影响脓毒症的炎症反应。该假设将通过追求三个具体目标来检验：1）确定脓毒症儿童单核细胞中 PPARg 通路的改变； 2）确定PPARg配体对脓毒性休克儿童离体单核细胞炎症反应的治疗效果； 3) 确定 PPARg 在肥胖者败血症易感性增加中的作用。在目标 1 下，我们将利用临床方法来研究脓毒症儿童外周血单核细胞中 PPARg 的变化。目标 2 将使用离体单核细胞的转化方法来研究 PPARg 配体在改变脓毒症炎症反应中的治疗功效。目标 3 将使用基础科学方法，通过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。拟议的研究意义重大，因为它可以为脓毒症患者带来新的疗法，包括 FDA 批准的 PPARg 配体噻唑烷二酮的潜在用途，它可以增强 PPARg 通路。