The Role of Intermediate Filaments in Inflammation

摘要：中间丝是一种高度保守的真核细胞骨架蛋白，存在于 几乎体内的每一个细胞。尽管最初被认为是简单地为细胞提供结构支撑， 由于中间纤维与多种生物过程有关，它们现在被认为是一种 大量的蛋白质相互作用。由于中间纤维单体的数量，超过 70在人类中，其调控的复杂性，超过100个翻译后修饰 在我们对它们被调控的分子机制的理解上仍然存在差距 并通过它们对许多生物过程做出贡献。为了开始填补这些空白，我们寻求 为了确定细胞中调节中间丝的分子机制，并 通过关注中间纤维在中性粒细胞中的作用，确定中间纤维如何促进炎症 炎症过程和迁移。这项建议建立在PIS以往经验的基础上 细菌感染过程中中间丝功能的研究 建立筛选永生化中性粒细胞群体的新细胞模型 PI成功地使用这些方法来定义中间体 细丝波形蛋白参与炎症过程。它在资金方面提供的灵活性 R35计划将使PI能够灵活地跟踪最有希望的调查路线 并利用提出的方法在实验室内培训初级科学家。这个 成功完成拟议的研究极有可能改善我们的一般情况 对细胞中中间丝起作用的生物过程的理解 以及我们对中性粒细胞功能调节机制的理解 发炎。

Abstract: Intermediate filaments are highly conserved eukaryotic cytoskeletal proteins present in nearly every cell in the body. Although initially thought to simply provide structural support to cells, intermediate filaments are now implicated in a variety of biological processes due to their numerous protein interactions. Due to the number of intermediate filament monomers, more than 70 in humans, and the complexity of their regulation, more than 100 posttranslational modification sites, gaps remain in our understanding of the molecular mechanisms by which they are regulated and by which they contribute to many biological processes. To begin to fill these gaps, we seek to define molecular mechanisms by which intermediate filaments are regulated in cells and to define how intermediate filaments contribute to inflammation by focusing on their role in neutrophil inflammatory processes and migration. This proposal builds on the PIs previous experience investigating intermediate filament function during bacterial infection by proposing to leverage new cellular models of immortalized neutrophil populations with established screening approaches successfully use by the PI to define molecular mechanisms by which the intermediate filament vimentin contributes to inflammatory processes. The flexibility in funding provided by this R35 program will enable the PI the flexibility to follow the most promising lines of investigation and to leverage the proposed approaches to train junior scientists within the laboratory. The successful completion of the proposed studies is highly likely to improve our general understanding about the biological processes in cells to which intermediate filaments contribute and to our understanding of the mechanisms by which neutrophil function is regulated during inflammation.