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、骨折和输血的创伤性损伤释放促进全身性过度炎症的循环因子（如TNF α、IL-1和IPS）。这些试剂立即激活循环白细胞、内皮细胞和血管细胞上的信号受体，从而引发或改变这些细胞类型及其随后的反应。配体激活的受体从质膜表面发出信号的初始阶段由第二信使、离子流和在几分钟内发生的蛋白磷酸化介导。激活的受体募集衔接蛋白，通常与Ca++和局部膜组成的变化协调。一系列组装事件形成聚集的信号传导复合物，其构建多结构域蛋白质支架，所述支架同时进行内吞作用， 激活激酶模块如MAPK和IKK。这些模块导致转录组的许多持续变化，从而影响所有随后的细胞反应数小时或数天，包括细胞周期或凋亡。在白细胞中，MAPK模块调节促炎作用：超氧化物分泌、中性粒细胞中的脱粒、细胞因子和趋化因子的合成和释放。在血管内皮细胞和平滑肌细胞中，NF-κ B和AP-1上调白细胞粘附蛋白的表达，促进炎症和渗漏。 细胞生物学家已经知道，网格蛋白介导的内吞作用（CME）可以被阻断， 高渗和伯胺阻断（通过影响内体组装或破坏其成熟）。在几种转化细胞中，干扰CME通过生物活性介质（如儿茶酚、脂质和TNF α）阻止MAPK或NF-kB信号传导。然而，目前还不清楚CME加工的不同阶段如何通过哺乳动物，特别是人类细胞中的内化受体调节激酶信号传导。此外，原代细胞的结果是否反映了动物模型中的炎症信号？值得注意的是，复苏方面的进展表明，高渗对于防止促炎性启动具有额外的优势。另外，一些伯胺和微管效应器似乎有希望控制炎症。在本提案中，我们评估抑制内吞作用是否会影响一系列可归咎因子和细胞的内吞后信号传导。如果是，这些机制能否提出改进或替代办法？