Equipment Supplement request for an Octet RED96 biolayer interferometry instrument

Octet RED96 生物层干涉测量仪器的设备补充请求

• 批准号: 9027318
• 负责人: Chuanfu Li
• 金额: $ 8.95万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027318
• 关键词: Adult Respiratory Distress Syndrome; Attenuated; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Cell Communication; Cells; Clinical; Communicable Diseases; Communications Media; Complex; Complication; Critical Illness; Data; Disease; Employee Strikes; Equipment; Functional disorder; Gene Expression; Goals; Grant; Health; Heart failure; Infection; Inflammatory; Inflammatory Response; Injury; Interferometry; Investigation; Knowledge; Lipids; Literature; Mediating; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Multiple Organ Failure; Mus; Myocardial dysfunction; Nucleic Acids; Nucleotides; Organ; Outcome; PIK3CG gene; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphatidylinositols; Phosphotransferases; Play; Proteins; Publishing; Regulation; Regulator Genes; Research; Role; Sepsis; Sepsis Syndrome; Septic Shock; Signal Transduction; Testing; Toll-like receptors; Transgenic Mice; Treatment Efficacy; United States; Untranslated RNA; attenuation; base; heart cell; heart preservation; improved; instrument; macrophage; mortality; novel; particle; prevent; response; septic; small molecule

DESCRIPTION (provided by applicant): The critically ill patient frequently develops a complex disease spectrum that may include acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), sepsis syndrome and/or septic shock and multiple organ dysfunction syndrome (MODS). In the United States ~750,000 patients/year develop sepsis syndrome. Cardiovascular dysfunction is a major complication associated with the morbidity and mortality of sepsis. This clinical condition has been termed "septic cardiomyopathy". The mechanisms by which septic cardiomyopathy occur remain unclear. We and others have demonstrated that activation of Toll-like receptor (TLR) mediated NF-κB pathway plays a deleterious role in septic cardiomyopathy, while activation of phosphoinositide-3 kinase (PI3K)/Akt signaling protects against cardiac dysfunction in sepsis. However, the mechanisms by which modulation of cellular signaling determines the fate of cardiac function in sepsis are still unclear. During the last grant period, we discovered that microparticles isolated from septic mice significantly suppress cardiac function in normal mice and induce injury of macrophages. The effect of septic microparticles on cardiac function is similar to the cardiac dysfunction we have observed in a murine model of septic cardiopathy. Thus, microparticles released in response to sepsis may be an important pathologic mechanism of septic cardiomyopathy. Our findings suggest a new and novel concept that microparticles generated during sepsis contribute to cardiac dysfunction. In striking contrast, microparticles secreted by cells with activated PI3K/Akt signaling attenuate septic cardiomyopathy, suppress inflammatory responses and may contribute to improved outcome in sepsis. Based on these data we hypothesize that "microparticles generated in response to modulation of TLR/NF-κB and PI3K/Akt differentially regulate cardiac function, systemic inflammatory responses and survival outcome in sepsis". To test this hypothesis we propose three specific aims. Specific Aim 1 will elucidate the mechanisms by which the microparticles generated during polymicrobial sepsis induce septic cardiomyopathy. Specific aim 2 will define the protective mechanisms of microparticles released in response to activation of PI3K/Akt signaling in septic cardiomyopathy. Specific aim 3 will investigate the therapeutic efficacy of 10MER3 a synthetic, small molecule which stimulates the release of microparticles that attenuate septic cardiomyopathy, inhibits the inflammatory phenotype and improves survival outcome in sepsis. The long term goals of this competitive renewal application are to elucidate the cellular and molecular mechanisms of septic cardiomyopathy and to develop new and novel therapies to ameliorate the morbidity and mortality associated with sepsis induced cardiac dysfunction.

描述（由适用提供）：重症患者经常发展出复杂的疾病谱，其中可能包括急性呼吸窘迫综合征（ARDS），全身性炎症反应综合征（SIRS），败血症综合征和/或败血性休克以及多器官功能障碍综合征（MODS）。在美国，约75万名患者/年发育败血症综合症。心血管功能障碍是与败血症的发病率和死亡率相关的主要并发症。该临床状况已被称为“败血性心肌病”。败血性心肌病的机制尚不清楚。我们和其他人已经证明，Toll样受体（TLR）介导的NF-κB途径的激活在败血性心肌病中起着有害作用，而磷酸肌醇3激酶（PI3K）/AKT激活的激活在SEPIS中可以防止心脏功能障碍。然而，尚不清楚细胞信号调节决定心脏功能的命运的机制。在最后一个赠款期间，我们发现从化粪池小鼠中分离出的微粒可显着抑制正常小鼠的心脏功能，并诱导巨噬细胞的损伤。化粪池微粒对心脏功能的影响类似于我们在败血性心脏病的鼠模型中观察到的心脏功能障碍。这是对败血症释放的微粒可能是化脓性心肌病的重要病理机制。我们的发现提出了一个新的新颖概念，败血症期间产生的微粒导致心脏功能障碍。在打击对比中，由活化的PI3K/AKT信号传导分泌的微粒减弱了化脓性心肌病，抑制炎症反应，并可能有助于改善败血症的预后。基于这些数据，我们假设“根据TLR/NF-κB和PI3K/AKT的调节，生成的微粒对败血症中的心脏功能，全身性炎症反应和存活结果进行了差异调节”。为了检验这一假设，我们提出了三个具体目标。具体的目标1将阐明在多菌血性败血症期间产生的微粒诱导败血性心肌病的机制。特定的目标2将定义因败血性心肌病中PI3K/AKT信号的激活而释放的微粒的保护机制。具体目标3将研究10Mer3的治疗效率A合成小分子，该分子刺激衰减败血性心肌病的微粒释放，抑制炎症表型并改善脓毒症的生存结果。这种竞争性更新应用的长期目标是阐明败血性心肌病的细胞和分子机制，并开发出新的和新颖的疗法以减轻与败血症诱发心脏功能障碍相关的发病率和死亡率。