# BLR&D Research Career Scientist Award Application

> **NIH VA IK6** · VA  MEDICAL CENTER · 2024 · —

## Abstract

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...

## Key facts

- **NIH application ID:** 10789129
- **Project number:** 2IK6BX004479-06
- **Recipient organization:** VA  MEDICAL CENTER
- **Principal Investigator:** XUE-RU WU
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2018-10-01 → 2030-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10789129

## Citation

> US National Institutes of Health, RePORTER application 10789129, BLR&D Research Career Scientist Award Application (2IK6BX004479-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10789129. Licensed CC0.

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