# BLR&D Research Career Scientist Award Application

> **NIH VA IK6** · VA  MEDICAL CENTER · 2021 · —

## Abstract

This renewal application for Research Career Scientist (RCS) award seeks to continue the ongoing research
activities by the incumbent that have been focused on the molecular pathogenesis of major urinary tract
diseases including bladder cancer and kidney stone. Both diseases are highly prevalent among the Veterans,
and inflict considerable emotional and physical suffering and staggering medical expenses. Despite the
socioeconomic impact, research into the molecular pathogenesis of these diseases remains extremely limited,
thus hampering the development of new diagnostic, therapeutic and preventive strategies. During the last
award period, the laboratory of the RCS has made significant inroads in defining the key genetic and
epigenetic determinants underlying the initiation and progression of bladder cancer and kidney stone. With
respect to bladder cancer, the laboratory of the RCS identified several specific combinatorial genetic drivers
that are responsible for the genesis and progression of the two major phenotypic variants of bladder cancer,
e.g., low-grade superficial papillary tumors versus high-grade invasive tumors. Using a broad range of
technical approaches including cultured cell lines, genetically engineered mice, chemical carcinogenesis,
analysis of human specimens and high-throughput profiling, the laboratory found that the activation of receptor
tyrosine kinase (RTK)/RAS/PI3K pathway collaborates with the loss of 9p21 tumor suppressors (e.g., CDKN2A
and CDKN2B) to induce low-grade superficial papillary bladder cancer, and that the same activated
RTK/RAS/PI3K pathway collaborates with the deficiency of RB family proteins or that of the p53 pathway
effectors to induce high-grade muscle-invasive bladder cancer. In another series of studies supported by a VA
Merit Review award, the laboratory of the RCS demonstrated that pyruvate kinase 2 (PKM2), a key enzyme in
anaerobic glycolysis or Warburg effect, is upregulated in most bladder cancers and plays a critical role in
bladder cancer cell proliferation, and that genetic ablation of PKM2 markedly reduces bladder cancer growth in
vitro and in vivo. Inhibition of PKM2 by RNAi or small molecules also greatly decreases the acquired resistance
of bladder cancer cells to cisplatin. These and other data to be detailed in the proposal are highly significant in
not only improving our understanding of the molecular bases of bladder cancer pathogenesis, but also offer
practical insights into novel strategies for bladder cancer diagnostics and treatment. With respect to kidney
stone, the laboratory of the RCS continued to make major progress in unraveling the role and mechanisms of
action of Tamm-Horsfall protein (THP or uromodulin), the most abundant urinary protein in humans, in urinary
tract defense against kidney stone formation. The deficiency of THP renders animal models more susceptible
to intra-renal calcification, via increased urinary supersaturation, that strongly resembles the early stage...

## Key facts

- **NIH application ID:** 10047291
- **Project number:** 5IK6BX004479-03
- **Recipient organization:** VA  MEDICAL CENTER
- **Principal Investigator:** XUE-RU WU
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10047291

## Citation

> US National Institutes of Health, RePORTER application 10047291, BLR&D Research Career Scientist Award Application (5IK6BX004479-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10047291. Licensed CC0.

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