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.
Oral mucositis is the most common side effect of cancer treatment strategies. In oral mucositis, uncontrolled expression of many growth- and inflammation-associated genes occurs. By better understanding the cellular mechanisms involved in controlling the expression of these factors, we expect that the work will lead to a better understanding of the mucositis formation which should subsequently lead to novel methods to stop or slow down oral mucositis.
|Talwar, Sudha; House, Reniqua; Sundaramurthy, Santhanalakshmi et al. (2014) Inhibition of caspases protects mice from radiation-induced oral mucositis and abolishes the cleavage of RNA-binding protein HuR. J Biol Chem 289:3487-500|