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1、Research Interest ProposalI am the Doctor degree applicant Xu Zhiwei. From September 2008 to June 2013, I studied the laboratory medicine at Nantong University. In September 2013 I was recommended to the graduate school by the professors due to my excellent assessment. Through undergraduate studies,
2、 I contacted such theories as molecular biology, cellular biology , immunology and so on. However, keenly conscious that my current acquisition is far from enough for me to meet the needs of the fast developing medicine, I am eager to pursue further studies in Chinese medical sciences. With my hard
3、working, I know about the basic knowledge of medical immunology. Up to now, I have known a lot about the University of Macau. The graduate school of university plays a prominent role in the academic research and transforms Macao into a knowledge-based society. I am dedicated to pursuiting medical re
4、search and hoping to come to the university of Macau for rich experiences and success in PhD program.I am now applying for Chinese Medical Science in the University.This planned research has the following aims:The deubiquitinating enzyme USP14 has been identified and biochemically studied, but its m
5、echanisms in cancer remains to be elucidated. Protein glycosylation with O-linked N-acetylglucosamine (O-GlcNAc) is a reversible post-translational modification occurring onserine or threonine residues. Intriguingly, it has been observedthat O-GlcNAcylation is particularly abundant on cancer cells.
6、The aim of this study was to evaluate the O-GlcNAcylation of USP14 in patients with cancer and to define its mechanisms in cancer cell proliferation and apoptosis.a. To demonstrate that O-GlcNAcylation of USP14.b. To explore Interplay between USP14 O-GlcNAcylation and phosphorylationc. To determine
7、how O-GlcNAcylation regulates metabolic reprogrammingand Signaling in cancer cells.d. To test whether O-GlcNAcylation regulates proliferation and apoptosis.2.Research ContextDeregulating cellular energetics is emerging as a characteristichallmark of cancer cells. Withinsuch cells, glucose and glutam
8、ine are used at an increasedrate, resulting in the production ofATP in a manner independent of oxygen concentration. Elevated glucose and glutamine flux areneeded not only to serve the energetic demands of cancer cells,but also to provide the essential carbon and nitrogen used inmacromolecule synthe
9、sis, fueling the rapid growth and proliferation seen in tumors. This increasein glucose and glutamine uptake can alter multiple metabolicand signaling pathways in cancer cells, including for examplethe hexosamine biosynthetic pathway (HBP). The HBP relies on glucose and glutamine uptake, and approxi
10、mately 3%5% of the total glucose entering a cell is shunted intothis pathway. This critical metabolite isrequired for the biosynthesis of a variety of extracellular glycopolymers, including both N- and O-glycans, however, it also serves as the substrate for O-linked b-N-acetlyglucosamine (O-GlcNAc)
11、transferase (OGT). O-GlcNAcylation is directly involved in growth hormone (gibberellic acid) signalling in plants, and both SPY and SECRET AGENT(SEC) encode O-GlcNAc transferases. Mutations in either SPY or SECcause severe growth defects; simultaneous mutation of both genes islethal. Unlike plants,
12、mammals and insects seem to have only a single gene encoding the catalytic subunit of the O-GlcNAc transferase(OGT) Gene disruption in mice established that OGT is required forembryonic-stem-cell viability20. Tissue-targeted disruption in miceshowed that O-GlcNAcylation is essential to several cell
13、types. OGTdeletion causes hyperphosphorylation, which is followed by cell death, induces T-cell apoptosis and causes growth arrest infibro blasts. Crelox-mediated deletion of OGT in cultured fibroblastsresults in death as pre-existing OGT protein levels diminish. This modification can be removed by
14、theglycoside hydrolase O-GlcNAcase (OGA) that catalyzes cleavage of O-GlcNAc from proteins. This modification can alter protein functiondirectly or, in some cases, by competing with phosphorylationsites. O-GlcNAc and O-phosphate site-mapping studies suggest that there areat least four different type
15、s of dynamic interplay between O-GlcNAcand O-phosphate . First, there is competitive occupancy at thesame site, for example that which occurs in the transcription factorc-Myc25 and oestrogen receptor-26, and on the oncoprotein SV-40 largeT-antigen27 and endothelial nitric oxide synthase28. Second, c
16、ompetitiveand alternative occupancy occur at adjacent sites, such as that observedin the tumour suppressor p53 and synapsin I. Third,there is a complex interplay whereby some O-phosphate attachmentsites on a given protein are the same as some O-GlcNAc sites, whereasothers are adjacent to, or even distant from, each other, such as on theC-terminal domain of RNA polymerase II and on cytokeratins32. The final type of interplay involves proteins in which this relat
