# The function of lysophosphatidic acid receptor LPA5R in intestinal inflammation and epithelial damage

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $507,002

## Abstract

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, affects 1-2 million people in
the United States, and is a significant financial burden for the country. IBD increases the risk factor for other
diseases such as colorectal cancer and atherosclerosis. Intestinal epithelial cells (IECs) form the physical barrier
that protects the body from the hostile environment of the gut, and damage to the intestinal epithelium leads to
the entry of noxious molecules and organisms, which activates the mucosal immunity. Lysophosphatidic acid
(LPA), a naturally occurring bioactive lipid, acts on a family of G protein-coupled receptors to mediate multiple
effects that can regulate survival and proliferation of various cell types. Of six known LPA receptors, LPA5R is
highly expressed in the gastrointestinal (GI) tract. A recent genome-wide association study (GWAS) for early on-
set of IBD identified a single nucleotide polymorphism within the GPCR GPR35. A subsequent study has shown
that LPA is an endogenous ligand of GPR35, linking aberrant LPA-mediated signaling to the pathogenesis of
IBD. Significant expression of LPA5R in the GI tract and the suggestion of aberrant LPA-mediated signaling
prompted us to generate a novel mouse model in which LPA5R can be deleted inducibly or constitutively.
Preliminary studies show that inducible deletion of LPA5R resulted in crypt IEC apoptosis, severe colitis, and
increased morbidity, without visible effects on villus IECs. In contrast, mice with constitutive deletion of LPA5R
appear normal, suggesting compensatory protection. Surprisingly, we found that crypt epithelial cells with
constitutive deletion of LPA5R are more resistant to ionizing radiation- or cytokine-induced apoptosis, suggesting
overcompensated cell survival. However, both constitutive and inducible deletion resulted in increased epithelial
permeability and decreased epithelial junctional protein expression in villus epithelium, suggesting that LPA5R
regulates epithelial barrier function. We hypothesize that LPA5R maintains the integrity of intestinal epithelium
by regulating survival of crypt epithelial cells and the epithelial barrier functions at the brush border. We will
investigate the underlying cause of IEC death upon LPA5R deletion and the role of LPA5R in IEC regeneration
(aim 1). We will determine the underlying mechanism for the compensatory increase in IEC survival in
constitutive deletion and test the hypothesis that overcompensated crypt cell survival promotes survival of
abnormal cells in response to stress (aim 2). Additionally, we will investigate that epithelial barrier dysfunction in
the absence of LPA5R that elevates intestinal inflammation and, together with increased IEC survival, increases
the susceptibility to colon neoplasia (aim 3). The proposed studies should reveal the novel functions of LPA5R
in the maintenance of intestinal epithelium. We anticipate that successful completion of this study will identi...

## Key facts

- **NIH application ID:** 9927619
- **Project number:** 5R01DK116799-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Changhyon Chris Yun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $507,002
- **Award type:** 5
- **Project period:** 2018-09-20 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927619

## Citation

> US National Institutes of Health, RePORTER application 9927619, The function of lysophosphatidic acid receptor LPA5R in intestinal inflammation and epithelial damage (5R01DK116799-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9927619. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*