# Deciphering the role of pH regulator Slc4a4 in glioma progression

> **NIH NIH K99** · BAYLOR COLLEGE OF MEDICINE · 2024 · $134,582

## Abstract

PROJECT SUMMARY. Malignant glioma is a devastating brain cancer with no improvements in prognosis over
decades. One key mechanism for glioma progression is the dynamic metabolic communication between the
tumor cells and the tumor microenvironment (TME). Although extracellular acidosis is a pathological hallmark of
TME, the precise pH-dependent mechanisms underlying glioma metabolic reprogramming remain poorly
defined. This proposal’s overarching goal is to discover the genes and pathways regulating glioma metabolism
and glioma-vascular crosstalk. This proposal focuses on Slc4a4, a glial-enriched sodium-bicarbonate
cotransporter that was previously identified as an intracellular and extracellular pH regulator. Slc4a4-mediated
pH regulation is important for glial-vascular interaction after injury, but its role in glioma progression is undefined.
To begin addressing this gap in knowledge, I analyzed The Cancer Genome Atlas (TCGA) database and found
that high Slc4a4 expression correlates with prolonged survival in glioma patients. Corroboratively, my preliminary
data showed that Slc4a4 gain of function (GOF) drastically decreases tumor growth and angiogenesis in patient-
derived xenograft and CRISPR-mediated de novo mouse glioma models, which is further complemented by loss-
of-function (LOF) studies using glial-specific Slc4a4 knockout mice. These data suggest an inhibitory role of
Slc4a4 in glioma and associated aberrant vascular remodeling. Multi-omic profiling of Slc4a4 GOF/LOF mouse
glioma found that Slc4a4 negatively regulates the expression of a key lipid binding protein, fatty acid binding
protein 5 (FABP5), which is coupled with dysregulated lipid metabolism. Further analysis of the TCGA database
showed an inverse expression and survival correlation between Slc4a4 and FABP5 in glioma patients. In an
immunocompetent mouse glioma model, FABP5 overexpression reverses Slc4a4’s inhibitory effects on glioma
growth, suggesting an antagonistic Slc4a4-FABP5 axis in glioma. Finally, comprehensive transcriptomic profiling
of Slc4a4 GOF/LOF glioma revealed dysregulated gene signatures involved in acidic pH response, lipid
metabolism, and endothelial function. Based on these preliminary data, my central hypothesis is that Slc4a4
suppresses glioma progression, in part by regulating lipid metabolism and glioma-vascular interaction. To test
this hypothesis, I will first define Slc4a4’s role in glioma progression (Aim 1). Next, I will determine how Slc4a4
inhibits gliomagenesis via reprogramming intrinsic glioma lipid metabolism (Aim 2). Upon completion of Aims 1
and 2 in the K99 phase, I will establish Slc4a4’s role in glioma progression and associated lipid dysregulation. In
the R00 phase, I will determine how Slc4a4 mediates glioma-vascular interaction with a focus on endothelial
metabolism (Aim 3). The proposed studies will define the pH-dependent mechanisms by which glioma hijacks
brain vasculature to progress, ultimately establishing an independent res...

## Key facts

- **NIH application ID:** 10984807
- **Project number:** 1K99CA295327-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Qi Ye
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $134,582
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10984807

## Citation

> US National Institutes of Health, RePORTER application 10984807, Deciphering the role of pH regulator Slc4a4 in glioma progression (1K99CA295327-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10984807. Licensed CC0.

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