Vulnerability to sepsis in old age

老年时容易患败血症

基本信息

批准号：
7415043
负责人：
Hiroshi Saito
金额：
$ 21.05万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-15 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7415043
关键词：
Accounting Affect Age Aging Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Cause of Death Cessation of life Characteristics Clinical Trials Coagulants Coagulation Process Doctor of Philosophy Elderly Endotoxemia Endotoxins Enzymes Foundations Functional disorder Future Gene Expression Genes Goals Heart Homeostasis Incidence Infection Inflammation Inflammatory Injection of therapeutic agent Intensive Care Units Intervention Intra-abdominal Kidney Ligation Lipopolysaccharides Liver Lung Mediator of activation protein Messenger RNA Modeling Morbidity - disease rate Multiple Organ Failure Mus Mutant Strains Mice Organ Oxidative Stress Patients Population Proteins Puncture procedure Research Research Personnel Risk Role Saline Sepsis Sepsis Syndrome Septic Shock Spleen Testing Tissues age effect aged base improved innovation interest juvenile animal middle age mortality mouse model novel therapeutics older patient research study response septic

项目摘要

DESCRIPTION (provided by applicant): Sepsis is an infection-initiated manifestation of the systemic inflammatory response syndrome that often progresses to septic shock, multiple organ failure with high risks of death. Sepsis is a particularly serious problem in the geriatric population, as the elderly patients with sepsis suffer much higher morbidity and mortality than younger patients. In fact, sepsis is a major cause of death in elderly patients at intensive care units in the US. Although this problem is increasingly recognized, the underlying mechanism(s) responsible for this age-associated vulnerability remain largely unknown. The long-term goal of our research is to determine the mechanisms responsible for the increased septic vulnerability in the aged, and to use this information to develop new treatment strategies for sepsis. The age-associated vulnerability to sepsis is also seen in animal models. We have shown that aged mice suffer significantly higher mortality than young mice in two commonly used models for sepsis; endotoxemia induced by bacterial lipopolysaccharide injection, and an intra-abdominal sepsis induced by cecal ligation and puncture. We have also found that the elevated mortality in aged mice is associated with altered inflammatory and coagulation responses, and increased oxidative damages. Our central hypothesis is that loss of homeostasis in old age leads to excessive inflammation, oxidative damage, and coagulation, contributing to the age-associated vulnerability to sepsis. Our objective in this project is to define the age-associated alterations in pathophysiology and gene expression in the mouse model of sepsis, and to develop strategies to improve the survival of the old mice with sepsis. To achieve these goals, we pursue the following three specific aims: (1) To determine the effects of aging on the pathophysiology of sepsis, (2) To identify the age-associated alterations in gene expression that affects mortality in sepsis, and (3) To test likely strategies for their ability to decrease age-associated mortality in sepsis. The information obtained from this project should provide the basis for new therapeutic strategies to substantially decrease the mortality in elderly patients with sepsis.

描述（由申请人提供）：败血症是全身性炎症反应综合征的感染引起的表现，通常会发展为败血性休克，多器官衰竭，并具有高死亡风险。脓毒症在老年人群中是一个特别严重的问题，因为败血症的老年患者的发病率和死亡率比年轻患者高得多。实际上，败血症是美国重症监护病房老年患者的主要死亡原因。尽管这个问题越来越被认可，但负责这种与年龄相关的脆弱性的基本机制在很大程度上尚不清楚。我们研究的长期目标是确定导致老年化粪池脆弱性增加的机制，并使用此信息来制定败血症的新治疗策略。在动物模型中也可以看到与年龄相关的败血症脆弱性。我们已经表明，在两个常用的败血症模型中，老年小鼠的死亡率明显高于年轻小鼠。通过细菌脂多糖注射引起的内毒素血症，以及由盲肠结扎和穿刺诱导的腹腔内败血症。我们还发现，老年小鼠的死亡率升高与炎症和凝结反应的改变以及氧化损伤增加有关。我们的中心假设是，老年稳态的丧失会导致过度炎症，氧化损伤和凝结，这导致了与年龄相关的败血症脆弱性。我们在该项目中的目标是定义败血症小鼠模型中与年龄相关的病理生理学和基因表达的变化，并制定策略以提高与败血症的旧小鼠的生存。为了实现这些目标，我们追求以下三个特定目的：（1）确定衰老对败血症病理生理学的影响，（2）确定基因表达的年龄相关的变化，影响败血症的死亡率，以及（3）测试其降低SEPSIS年龄相关死亡率的可能策略。从该项目获得的信息应为新的治疗策略提供基础，以大大降低老年败血症患者的死亡率。