The Role of Adipose Tissue in Age-dependent Sensitivity to Critical Illness

脂肪组织在年龄依赖性危重疾病敏感性中的作用

• 批准号: 8187763
• 负责人: Hiroshi Saito
• 金额: $ 30.44万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8187763
• 关键词: Abbreviations; Acute; Adipose tissue; Age; Age Reporting; Aging; Animal Model; Blood Coagulation Factor; Body fat; Burn Trauma; Cessation of life; Coagulants; Coagulation Process; Complication; Critical Illness; Death Rate; Development; Disease Resistance; Disseminated Intravascular Coagulation; Elderly; Endotoxemia; Endotoxins; Excision; Foundations; Functional disorder; Gene Expression; Genes; Genetic; Goals; Growth Factor; Health Care Costs; Hormones; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Interleukin-1 Receptors; Interleukin-6; Intra-abdominal; Knockout Mice; Ligation; Link; Lipopolysaccharides; Lung; Measures; Mediating; Mediator of activation protein; Methods; Modeling; Mus; Operative Surgical Procedures; Organ; Organ Culture Techniques; Pathway interactions; Patients; Pattern; Plasminogen Activator Inhibitor 1; Plasminogen Activator Inhibitor 2; Plasminogen Inactivators; Play; Predisposition; Preventive; Process; Production; Public Health; Puncture procedure; Role; Sepsis; Sepsis Syndrome; Severities; Signaling Protein; Source; Stress; System; TNF gene; Testing; Therapeutic; Thromboplastin; Thrombosis; Transgenic Organisms; Transplantation; Visceral; Visit; Wild Type Mouse; acute pancreatitis; age related; aged; biological adaptation to stress; cytokine; dietary restriction; effective therapy; improved; insight; middle age; mortality; mouse model; mutant; neglect; older patient; research study; therapy development

DESCRIPTION (provided by applicant): Aging is characterized by an altered stress response that underlies a compromised resistance to disease or injury. Activation of inflammatory and coagulant pathways is a frequent consequence of severe critical illnesses and results in the progression of systemic inflammatory response syndrome (SIRS). Recent evidence suggests that adipose tissue-derived signaling proteins, including cytokines, coagulation factors and hormones, may play an important role in the inflammatory response. Our long-term goals are to identify the mechanisms by which adipose tissue contributes to age-dependent severity of SIRS and to develop therapeutic strategies for decreasing vulnerability to critical illnesses in the aged. For these studies we will use two widely accepted mouse models of SIRS - acute endotoxemia induced by injection with bacterial endotoxin lipopolysaccharide and an intra-abdominal sepsis model induced by cecal ligation and puncture. The objective of this project is to identify and evaluate the expression of adipose-derived inflammatory and coagulant factors that differ by aging upon inflammatory stress. Our central hypothesis is that expression patterns of inflammatory / coagulant factors in the adipose tissue during SIRS are significantly altered by aging and that this alteration contributes to age-dependent severity of critical illnesses. To achieve the above goals, we will pursue the following three specific aims: (1) To define the role of adipose tissue in age-related alterations of coagulation during critical illness. (2) To understand the mechanisms of age-related inflammatory cytokine production in the adipose tissue during critical illness. (3) To evaluate methods of body fat loss as potential therapies and preventative measures for reducing severity of critical illness in the aged. These studies will provide significant insight into the association of the previously neglected adipose organ in aging and critical illness. PUBLIC HEALTH RELEVANCE: This project is relevant to public health because it will enhance our understanding of the roles of adipose tissue in increased severity of critical illness in the elderly. This project will also provide information for the development of treatments and preventative therapies to decrease incidence rates and deaths related to critical illness in the aged. Preventative therapies will likely result in reduced patient visits and decreased health care costs. The development of effective treatments for systemic inflammation, of which there are currently none available, will be beneficial to elderly patients who suffer from critical illnesses.

描述(由申请人提供)：衰老的特征是一种改变的应激反应，这是对疾病或伤害抵抗力下降的基础。炎症和凝血通路的激活是严重危重疾病的常见后果，并导致全身炎症反应综合征(SIRS)的进展。最近的证据表明，脂肪组织衍生的信号蛋白，包括细胞因子、凝血因子和激素，可能在炎症反应中发挥重要作用。我们的长期目标是确定脂肪组织促进年龄依赖性SIRS严重程度的机制，并开发治疗策略，以降低老年人对危重疾病的易感性。在这些研究中，我们将使用两种被广泛接受的SIRS小鼠模型--注射细菌内毒素内毒素诱导的急性内毒素血症和盲肠结扎和穿孔诱导的腹内脓毒症模型。该项目的目的是确定和评估脂肪来源的炎症和凝血因子的表达，这些因子随着年龄的增长而在炎症应激中有所不同。我们的中心假设是，SIRS期间脂肪组织中炎症/凝血因子的表达模式随着年龄的增长而显著改变，这种改变有助于危重疾病的年龄相关性严重程度。为了实现上述目标，我们将追求以下三个具体目标：(1)明确脂肪组织在危重疾病期间与年龄相关的凝血变化中的作用。(2)了解危重病期间脂肪组织中与年龄相关的炎性细胞因子的产生机制。(3)评价减脂方法作为降低老年人危重疾病严重程度的潜在治疗方法和预防措施。这些研究将为以前被忽视的脂肪器官与衰老和危重疾病的关联提供重要的洞察力。 公共卫生相关性：该项目与公共卫生相关，因为它将增强我们对脂肪组织在老年人危重疾病加重中的作用的理解。该项目还将为开发治疗和预防性治疗提供信息，以减少与老年人危重疾病有关的发病率和死亡率。预防性治疗可能会减少患者就诊次数，降低医疗成本。开发有效的全身炎症治疗方法将有利于患有危重疾病的老年患者。目前尚无有效的治疗方法。