# Identifying targetable mechanisms of TMEM38B/TRIC-B in liver fibrosis

> **NIH NIH R03** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $158,500

## Abstract

ABSTRACT:
Liver fibrosis impacts millions of people globally, with no pharmacologic therapies available to limit fibrosis
progression or promote fibrosis regression. The major fibrogenic cells in the liver are Hepatic Stellate Cells
(HSCs). Upon liver injury, activated HSCs produce and secrete fibrogenic proteins, including collagen Iα1 and
1α2, which are major component of fibrotic scarring in the liver. Several therapies have aimed to target HSCs
to limit fibrogenesis by preventing HSC activation or promoting HSC apoptosis; however these strategies have
not been successful in the clinic. We propose that understand the procollagen I trafficking machinery would
provide a unique and viable strategy for limiting fibrosis. We performed single cell RNA sequencing on
fibrogenic HSCs from mice and found upregulation of the understudied gene TMEM38B in fibrogenic HSCs.
TMEM38B is implicated in procollagen I trafficking in bone-producing osteoblasts, and mutations in TMEM38B
leads to brittle bones in mice and humans. We hypothesize that TMEM38B is critical for fibrogenesis through
mediating procollagen I trafficking and HSC survival, and that targeting TMEM38B could serve as a viable anti-
fibrotic strategy. Our preliminary data highlights a key role for TMEM38B in fibrogenesis. TMEM38B expression
is increased in patients where liver fibrosis has progressed to cirrhosis, as well as in murine models of liver
fibrosis. Secondly, TMEM38B is increased in primary human and mouse HSCs following activation with the
pro-fibrotic cytokine TGFβ. Finally, we show that TMEM38B is negatively regulated by the Polycomb
Repressor Complex 2 (PRC), a histone methyltransferase complex dysregulated in fibrosis. Disruption of the
PRC2 complex leads to increased TMEM38B expression in HSCs, and increased procollagen I deposition in a
murine model where key components of the PRC2 complex are deleted from osteoblasts. The experiments
proposed here will increase our understanding of TMEM38B in 3 critical areas: 1) Elucidating the critical
contribution of TMEM38B to fibrogenic processes, including procollagen I secretion and HSC survival, 2)
interrogating the critical domains and post-translational regulation of TMEM38B channel activity, and 3)
revealing mechanisms that regulate TMEM38B expression. Completion of the proposed research will provide
crucial insight into TMEM38B function and regulation under both physiological and pathophysiological
conditions as well as provide novel reagents to share with the research community, with the long term goal of
targeting TMEM38B as an anti-fibrotic strategy.

## Key facts

- **NIH application ID:** 10216441
- **Project number:** 1R03TR003641-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Jessica L Maiers
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $158,500
- **Award type:** 1
- **Project period:** 2021-05-15 → 2022-05-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216441

## Citation

> US National Institutes of Health, RePORTER application 10216441, Identifying targetable mechanisms of TMEM38B/TRIC-B in liver fibrosis (1R03TR003641-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10216441. Licensed CC0.

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