The present application is submitted to renew the Research Career Scientist (RCS) status of the incumbent in order to continue and expand his urological research that has strong relevance to the Veterans health, provide important services to the local and national VA, mentor the next-generation urological researchers and enhance the interdisciplinary collaborations of the RCS with investigators at the VA, academic affiliate and urological community at large. The renewal proposal is built upon the significant accomplishments the RCS has made during the last award cycle in all the aforementioned areas. On the scientific front, the RCS led his colleagues in re-defining the in vivo effects of the loss of tumor suppressors located at chromosome 9p21.3 on bladder tumor formation. Instead of the conventionally suspected loss of CDKN2A and ARF tumor suppressors, it is the loss of commonly neglected CDKN2B that triggers the tumor initiation of low-grade, non- invasive bladder cancer which accounts for 70-80% of all bladder cancers. Multiple lines of evidence from bladder tumor cell lines, genetic engineered mice and human specimens showed that the loss of CDKN2B markedly accelerates cell-cycle progression and releases the inhibition of CDKN2B on alpha enolase, an enzyme critical for aerobic glycolysis (Warburg effect). Structural work further demonstrates that the divergent amino acid sequences between CDKN2B and CDKN2A underlie their functional differences, making the former a significantly stronger tumor suppressor than the latter. These paradigm-changing findings have major implications on a new combinatorial biomarker set for accurately diagnosing and predicting the progression and preventing the recurrence of superficial papillary bladder tumors. On another notable series of studies, the RCS and colleagues found that, while the isoform 2 of pyruvate kinase (PKM2), which is universally overexpressed in bladder cancers, is not involved in bladder cancer initiation, it is indispensable for bladder growth and maintenance. PKM2 binds STAT3, and transcriptionally activates angiogenic factor HIF1alpha, and promotes non-oncogenic metabolic addiction. Taken together, the metabolic reprogramming through the upregulation of alpha enalose and PKM2 is crucial for bladder tumor initiation and progression, respectively, and inhibition of both glycolytic enzymes should be of significant values in controlling bladder cancers. The RCS and his collaborators at the VA and academic institutions have continued to deepen their understanding of the physiological functions and disease involvement of Tamm-Horsfall protein (uromodulin), the most abundant protein in human urine, in kidney stone formation, urinary tract infection, acute kidney injury and chronic kidney disease. They are actively embarking on the in vivo effects of the rare and common variants of uromodulin on monogenic and polygenic disorders using cutting-edge mouse modeling techniques. Over the last four and a...