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

描述（由申请人提供）：衰老的特征是应激反应的改变，其基础是对疾病或损伤的抵抗力降低。炎症和凝血途径的激活是严重危重疾病的常见后果，并导致全身性炎症反应综合征（SIRS）的进展。最近的证据表明，脂肪组织来源的信号蛋白，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对SIRS年龄依赖性严重程度的影响机制，并制定治疗策略，以减少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——注射细菌内毒素脂多糖诱导的急性内毒素血症和盲肠结扎穿刺诱导的腹腔脓毒症模型。该项目的目的是识别和评估脂肪源性炎症因子和凝血因子的表达，这些因子在炎症应激下因年龄而异。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，这种改变导致了危重疾病的年龄依赖性严重程度。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改变中的作用。(2)了解危重期脂肪组织中年龄相关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和预防措施。这些研究将为以前被忽视的脂肪器官在衰老和危重疾病中的关联提供重要的见解。

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.