Amelioration of Sepsis by Macrophage Activation

通过巨噬细胞激活改善脓毒症

• 批准号: 7497484
• 负责人: David L. Williams
• 金额: $ 28.71万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497484
• 关键词: 1-Phosphatidylinositol 4-Kinase; Abbreviations; Acute; Adult Respiratory Distress Syndrome; Apoptosis; Basic Science; Binding; Carbohydrates; Cell Proliferation; Class; Complex; Critical Illness; Data; Development; Disease; Enzymes; Event; Family; Feedback; Glucans; Glycogen; Goals; Grant; Homeostasis; Homologous Gene; ITAM; ITGAM gene; Immune response; Immunocompetent; Inflammation; Inflammatory; Inflammatory Response; Injury; Knowledge; Ligands; Ligation; Link; Macrophage Activation; Macrophage-1 Antigen; Membrane; Molecular; Morbidity - disease rate; Mus; Myelogenous; Newborn Respiratory Distress Syndrome; Nuclear; Outcome; PDPK1 gene; PTEN gene; Pathway interactions; Patients; Pattern recognition receptor; Phenotype; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphotransferases; Physiological; Play; Proto-Oncogene Proteins c-akt; Puncture procedure; RAC-Alpha Serine/Threonine Kinase; Receptor Signaling; Reporting; Research; Research Personnel; Resistance; Role; SR-A proteins; Sepsis; Sepsis Syndrome; Septic Shock; Signal Pathway; Signal Transduction; Splenocyte; Stream; Surface Plasmon Resonance; TNF receptor-associated factor 6; TRAF6 gene; Toll-Like Receptor 2; Toll-like receptors; Tyrosine; cytokine; dectin 1; improved; inositol-1,4,5-trisphosphate 5-phosphatase; novel therapeutics; prevent; receptor; response; scavenger receptor; septic; tensin; trafficking

DESCRIPTION (provided by applicant): The critically ill patient frequently develops a complex disease spectrum that may include adult respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), sepsis syndrome and/or septic shock. At present, we do not understand the cellular and molecular mechanisms that are involved in the initiation and propagation of septic injury; nor do we understand the innate physiologic mechanisms that attempt to limit inflammation maintain homeostasis and promote survival in the septic patient. The phosphoinsitide 3-kinases/Akt (PI3K/Akt) is a conserved family of signal transduction enzymes which are involved in regulating cellular proliferation and survival. During the last grant period, we discovered that the PI3K family of signal transduction enzymes plays an important physiologic role by limiting the inflammatory response to plymicrobial sepsis. Specifically, endogenous PI3K suppresses pro-inflammatory cytokine release and apoptosis in the septic host. It also promotes survival in fulminating sepsis. Of greater significance, we discovered that a carbohydrate ligand that is bound by membrane associated pattern recognition receptors stimulates the PI3K/Akt pathway resulting in decreased morbidity and increased survival outcome in fulminating sepsis. These data suggest that stimulation of the PI3K pathway may be an effective approach for preventing and/or treating sepsis/septic shock. In the current proposal, we will extend these studies to examine the cellular and molecular mechanisms by which glucan ligands stimulate PI3K/Akt signaling. We will focus on understanding the ligand-receptor interactions that activate PI3K, the postreceptor signal transduction events that stimulate PI3K/Akt/GSK3 and the cellular changes that culminate in modulation of PI3K and induction of the protective phenotype in sepsis injury. Not only will the results of this research increase our basic science knowledge of the innate response to inflammatory/septic disease, but it may also result in the development of new treatment strategies for several important disease states.

描述（由申请人提供）：危重患者经常出现复杂的疾病谱，可能包括成人呼吸窘迫综合征（ARDS）、全身炎症反应综合征（SIRS）、败血症综合征和/或败血性休克。目前，我们还不了解脓毒性损伤发生和传播的细胞和分子机制；我们也不了解试图限制炎症、维持体内平衡并促进脓毒症患者生存的先天生理机制。磷酸肌醇 3-激酶/Akt (PI3K/Akt) 是信号转导酶的保守家族，参与调节细胞增殖和存活。在上一次资助期间，我们发现信号转导酶 PI3K 家族通过限制多微生物败血症的炎症反应发挥着重要的生理作用。具体来说，内源性 PI3K 抑制脓毒症宿主中促炎细胞因子的释放和细胞凋亡。它还可以促进暴发性败血症的生存。更重要的是，我们发现与膜相关的模式识别受体结合的碳水化合物配体刺激 PI3K/Akt 途径，从而降低暴发性脓毒症的发病率并增加生存结果。这些数据表明，刺激 PI3K 通路可能是预防和/或治疗脓毒症/感染性休克的有效方法。在当前的提案中，我们将扩展这些研究，以检查葡聚糖配体刺激 PI3K/Akt 信号传导的细胞和分子机制。我们将重点了解激活 PI3K 的配体-受体相互作用、刺激 PI3K/Akt/GSK3 的受体后信号转导事件以及最终导致 PI3K 调节和败血症损伤中保护表型诱导的细胞变化。这项研究的结果不仅会增加我们对炎症/化脓性疾病先天反应的基础科学知识，而且还可能导致针对几种重要疾病状态开发新的治疗策略。