POST-ENDOCYTOTIC INFLAMMATORY SIGNALING AFTER TRAUMA

创伤后内吞后炎症信号传导

• 批准号: 6919600
• 负责人: ANIRBAN BANERJEE
• 金额: $ 16.22万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919600
• 关键词: biological signal transduction; clathrin; endocytosis; enzyme activity; hemorrhagic shock; human tissue; immunopharmacology; inflammation; injury; interleukin 1; laboratory rat; lipopolysaccharides; mitogen activated protein kinase; protein kinase; protein localization; trauma; tumor necrosis factor alpha

Traumatic injury involving shock, tissue injury, fracture and transfusion, releases circulating factors (such as TNFalpha, IL-1 and IPS) that promote systemic hyper-inflammation. These agents immediately activate signaling receptors on circulating leukocytes, endothelium and vascular cells, thereby priming or altering these cell-types, and their subsequent responses. The initial phase of signaling by ligand activated receptor from the plasma membrane surface, is mediated by second messengers, ion-fluxes, and protein phosphorylation occurring within minutes. Activated receptors recruit adaptor proteins often coordinated with change in Ca++ and local membrane composition. A series of assembly events forms clustered signaling complexes that build-up multi-domain protein scaffolds which simultaneously conduct endocytosis and activate kinase modules such as MAPKs and IKK. These modules cause many sustained changes to the transcriptome, thereby affecting all subsequent cellular responses for hours or days, including cell-cycling or apoptosis. In leukocytes, MAPK modules regulate pro-inflammatory actions: superoxide secretion, and degranulation in neutrophils, synthesis and release of cytokines and chemokines. In vascular endothelial and smooth muscle cells, NF-kB and AP-1 upregulate expression of leuko-adhesive proteins, promoting inflammation and leak. Cell biologists have known that that clathrin-mediated endocytosis (CME) can be blocked by hypertonicity and primary amines block (by affecting endosome assembly or disrupting its maturation). In several transformed cells, interfering with CME prevents MAPK or NF-kB signaling by bioactive mediators (such as catechols, lipids and TNFalpha). However, it is unclear how the different stages of CME processing regulates kinase signaling by internalized receptors in mammalian, especially human, cells. Further, would the results in primary cells reflect inflammatory signaling in animal models? Remarkably, advances in resuscitation suggest that hypertonicity has additional advantages for preventing pro-inflammatory priming. Separately, some primary amines and microtubule effectors appear promising for inflammation control. In this proposal we assess whether suppressing endocytosis affects postendocytotic signaling for a permuted list of culpable agents and cells. If so, could the mechanisms suggest improvements or alternatives?

涉及休克，组织损伤，断裂和输血的创伤性损伤可释放循环因子（例如TNFALPHA，IL-1和IPS），从而促进全身性高炎。这些药物立即在循环白细胞，内皮和血管细胞上激活信号受体，从而启动或改变这些细胞类型及其随后的反应。配体从质膜表面激活的受体的信号传导的初始阶段是由第二个使者，离子 - 流通量和蛋白质磷酸化介导的，几分钟内发生。活化的受体募集适配器蛋白通常与Ca ++和局部膜组成的变化进行协调。一系列的装配事件形成了聚集的信号传导复合物，这些综合体积累了多域蛋白支架，同时进行内吞作用和 激活激酶模块，例如MAPK和IKK。这些模块会导致转录组的许多持续变化，从而影响了所有随后的细胞反应数小时或几天，包括细胞循环或凋亡。在白细胞中，MAPK模块调节促炎作用：超氧化物的分泌和中性粒细胞中的脱粒，合成和细胞因子和趋化因子的合成和释放。在血管内皮和平滑肌细胞中，NF-KB和AP-1上调白细胞粘附蛋白的表达，促进炎症和泄漏。 细胞生物学家知道网格蛋白介导的内吞作用（CME）可以通过 高渗性和原代胺阻滞（通过影响内体组装或破坏其成熟）。在几个转化的细胞中，干扰CME可防止生物活性介质（例如儿茶酚，脂质和TNFALPHA）的MAPK或NF-KB信号传导。但是，尚不清楚CME加工的不同阶段如何调节哺乳动物（尤其是人类）细胞中内部化受体的激酶信号传导。此外，原代细胞的结果会反映动物模型中的炎症信号传导吗？值得注意的是，复苏的进步表明，高渗性在防止促炎性启动方面具有额外的优势。另外，一些原代胺和微管效应子似乎可以控制炎症。在此提案中，我们评估抑制性内吞作用是否会影响可抑制剂和细胞列表的内膜细胞信号传导。如果是这样，这些机制可以提出改进还是替代方案？