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（由申请方提供）：危重患者经常出现复杂的疾病谱，可能包括急性呼吸窘迫综合征（ARDS）、全身炎症反应综合征（SIRS）、脓毒症综合征和/或脓毒性休克和多器官功能障碍综合征（MODS）。在美国，每年约有750，000例患者发生脓毒症综合征。心血管功能障碍是与脓毒症发病率和死亡率相关的主要并发症。这种临床状况被称为“脓毒性心肌病”。脓毒性心肌病发生的机制尚不清楚。Toll样受体（TLR）介导的NF-κB通路的激活在脓毒症心肌病中起着有害的作用，而磷酸肌醇-3激酶（PI 3 K）/Akt信号通路的激活对脓毒症的心功能障碍具有保护作用。然而，脓毒症中细胞信号转导的调节决定心脏功能命运的机制仍不清楚。在上一个资助期，我们发现从脓毒症小鼠中分离的微粒显著抑制正常小鼠的心脏功能并诱导巨噬细胞损伤。脓毒性微粒对心脏功能的影响与我们在脓毒性心脏病小鼠模型中观察到的心功能障碍相似。因此，脓毒症时释放的微粒可能是脓毒症心肌病的重要病理机制。我们的研究结果提出了一个新的和新颖的概念，脓毒症过程中产生的微粒有助于心功能障碍。与此形成鲜明对比的是，由具有活化的PI 3 K/Akt信号传导的细胞分泌的微粒减轻脓毒性心肌病，抑制炎症反应，并可能有助于改善脓毒症的结果。基于这些数据，我们假设“响应TLR/NF-κB和PI 3 K/Akt的调节而产生的微粒差异性地调节脓毒症中的心脏功能、全身炎症反应和存活结果”。为了验证这一假设，我们提出了三个具体目标。具体目标1将阐明在多微生物败血症过程中产生的微粒诱导脓毒性心肌病的机制。具体目标2将定义脓毒性心肌病中响应于PI 3 K/Akt信号传导激活而释放的微粒的保护机制。具体目标3将研究10 MER 3的治疗功效，10 MER 3是一种合成的小分子，其刺激释放减轻脓毒症心肌病的微粒，抑制炎症表型并改善脓毒症的存活结果。该竞争性更新申请的长期目标是阐明脓毒症心肌病的细胞和分子机制，并开发新的和新颖的疗法，以改善脓毒症诱导的心功能不全相关的发病率和死亡率。