Mechanisms Of RNA-Binding Protein-Mediated Apoptosis In Oral Mucositis

描述（由申请人提供）：我们提出的研究将确定通过RNA结合蛋白（RBP）改变口腔粘膜炎发展和进展的转录后调控，RBP是大多数真核细胞中基因表达的关键调控因子。这些蛋白质影响mRNA代谢的关键方面，包括核转运和细胞质输出、运输、储存、翻译和周转。首先，在各种RNA结合蛋白中，HuR是影响细胞对应激、增殖和凋亡的反应的突出蛋白。 信号免疫触发和发育线索HuR编码许多炎症和凋亡相关的mRNA，包括细胞因子、白细胞介素和促凋亡因子，这些都是我们打算研究的下游靶点。鉴于HuR对这些关键调节剂表达的影响，我们对HuR蛋白结合mRNA以及它们在化学-放射治疗下如何调节很感兴趣。因此，我们的总体目标是破译蛋白质HuR如何影响口腔粘膜炎基因的表达在化疗-放疗。其次，口腔粘膜炎启动HuR的翻译后修饰，这反过来又通过mRNA稳定性促进炎症和凋亡。有趣的是，HuR在化疗下经历切割修饰;因此，我们试图了解化疗期间HuR切割是否在HuR与mRNA的关联中是重要的。最后，我们将测试HuR的过表达是否通过mRNA周转途径抑制炎症和细胞凋亡来保护口腔粘膜炎。因此，我们的数据将为了解HuR在口腔黏膜炎相关基因调控中的作用提供基础，并将成为未来HuR相关口腔疾病研究的关键。

DESCRIPTION (provided by applicant): Our proposed research will determine the post-transcriptional regulation that changes oral mucositis development and progression via RNA binding proteins (RBPs), which are critical regulators of gene expression in most eukaryotic cells. These proteins influence key aspects of mRNA metabolism including nuclear transit and cytoplasmic export, transport, storage, translation, and turnover. First, among various RNA- binding proteins, HuR is a prominent protein influencing cellular response to stress, proliferative signals, immune triggers, and developmental cues. HuR encodes many inflammation and apoptosis-related mRNAs including cytokines, interleukins and pro-apoptotic factors which are downstream targets we intend to study. Given HuR's influence on expression of these key modulators, we are intrigued about HuR protein binding mRNAs and how they are regulated under chemo-radiotherapy. Hence, our overall goal is to decipher how protein HuR influences oral mucositis gene expression during chemo-radiotherapy. Second, oral mucositis initiates post-translational modification of HuR which in turn, promotes inflammation and apoptosis through mRNA stability. Interestingly, HuR undergoes cleavage modifications under chemotherapy; hence, we seek to understand whether HuR cleavage during chemotherapy is important in HuR association with mRNAs. Finally, we will test whether overexpression of HuR protect oral mucositis through repressing inflammation and apoptosis through mRNA turnover pathway. Thus, our data will provide a foundation for understanding the role of HuR in oral mucositis-associated gene regulation and will be pivotal for future studies into HuR-associated oral diseases.