PIVOTAL ROLE OF PROTEASOMES IN INFLAMMATION AND TOLERANCE

蛋白酶体在炎症和耐受性中的关键作用

• 批准号: 8738686
• 负责人: Nilofer Qureshi
• 金额: $ 28.69万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8738686
• 关键词: Address; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation Pathway; Cell physiology; Cells; Chromatin; Cytokine Gene; Data; Deubiquitination; Development; Disease; Event; Exhibits; Galactosamine; Gene Activation; Gene Expression; Health; Healthcare; Human; Immune; Immune response; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Interferons; Knowledge; Laboratories; Ligands; Ligation; Lipopolysaccharides; Mediating; Mediation; Mediator of activation protein; Microbe; Modeling; Molecular; Morbidity - disease rate; Mus; NF-kappa B; Nitric Oxide; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Play; Process; Production; Proteasome Inhibition; Proteasome Inhibitor; Public Health; Puncture procedure; Recovery; Refractory; Regulation; Relative (related person); Research; Role; Sepsis; Septic Shock; Signal Pathway; Signal Transduction; Stimulus; Syndrome; TLR4 gene; TNF gene; Therapeutic; Therapeutic Intervention; Toll-like receptors; Ubiquitin; Ubiquitinated Protein Degradation; Ubiquitination; base; cytokine; effective intervention; innovation; insight; macrophage; monocyte; mortality; multicatalytic endopeptidase complex; novel; prevent; public health relevance; response; treatment strategy; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Septic shock remains as a major healthcare problem both in the U.S. and worldwide and, while the underlying mechanisms that contribute to disease are becoming increasingly well understood, there remain challenges in development of effective therapeutic interventions. The host response to potent inflammatory microbe- associated stimuli such as lipopolysaccharide (LPS), typically results in development of systemic inflammation, frequently referred to as a "syndrome of mediator excess". This response is typically followed by a transient state of relative refractoriness to further stimulation, historically termed tolerance. Recent results from this laboratory have contributed to the development of the novel concept that the innate immune response macrophage ubiquitin-proteasome pathway functions as a key regulator of LPS-induced signaling to regulate the inflammatory response through TLR4 in murine cells. The precise mechanisms that determine whether an inflammatory stimulus induces a proinflammatory cytokine response or a state of unresponsiveness/tolerance have not been dissected in human monocytes. Of particular potential importance is the status of the host innate immune in patients with SIRS/sepsis relative to normal individuals. Consequently, there is a critical need to delineate the intricate relationship between proteasome activity and differential regulation of signaling pathways in human monocytes/macrophages in health and disease, as new knowledge about these processes can ultimately be expected to facilitate development of innovative treatment strategies that target the proteasome. The central hypothesis is that development of inflammation vs. tolerance in human monocytes/macrophages in response to LPS is dictated by the profile of proteasomal protease and that these processes are disrupted during the development of SIRS/sepsis. Three Specific Aims, all based on strong preliminary data are proposed: 1. Identify mechanisms of selective proteasomal subunit-dependent mediation of LPS-induced inflammation. 2. Determine mechanism(s) by which selective proteasome subunits contribute to LPS-induced "tolerance/hyporesponsiveness." 3. Develop in vitro strategies to correct aberrant TLR responsiveness in human monocytes from SIRS/ sepsis patients. It is anticipated that the successful completion of the studies outlined in this proposal will ultimately contribute to development and implementation of therapeutic strategies to reduce morbidity and mortality of septic shock and, possibly, other cytokine-mediated diseases.

描述（由申请人提供）：在美国和全球范围内，败血性休克仍然是一个主要的医疗保健问题，尽管导致疾病的基本机制越来越充分地理解，但在开发有效的治疗干预措施方面仍存在挑战。宿主对有效的炎症性微生物相关刺激（例如脂多糖）（LPS）的反应通常会导致系统性炎症的发展，通常称为“介体过量综合征”。这种反应通常是在历史上被称为耐受性的相对折磨的瞬时状态。 该实验室的最新结果有助于新概念的发展，即先天免疫反应巨噬细胞泛素 - 蛋白酶体途径是LPS诱导的信号传导的关键调节剂，以调节鼠细胞中TLR4的炎症反应。确定炎症刺激的确切机制是否尚未在人的单核细胞中阐明促炎性细胞因子反应或无反应/耐受性的状态。与正常个体相对于正常人的SIR/败血症患者，宿主先天免疫的状态特别重要。因此，迫切需要描述蛋白酶体活动与人类单核细胞/巨噬细胞中信号通路的差异调节之间的复杂关系，因为最终可以期望对这些过程的新知识促进针对蛋白酶体的创新治疗策略的发展。中心假设是，响应于LP的炎症与耐受性的发展是蛋白酶体蛋白酶的特征决定的，并且在SIRS/SEPIS的发展过程中这些过程受到破坏。提出了三个基于强大初步数据的特定目标：1。确定选择性蛋白酶体亚基依赖性依赖LPS诱导的炎症的机制。 2。确定选择性蛋白酶体亚基有助于LPS诱导的“耐受性/低反应性”的机制。 3。制定体外策略，以纠正SIR/败血症患者的人类单核细胞中异常TLR反应性。预计该提案中概述的研究的成功完成将最终有助于制定和实施治疗策略，以降低败血性休克的发病率和死亡率以及其他细胞因子介导的疾病。