# Role of Beta Spectrin and Smad in Alcohol Induced Liver and GI Cell Proliferation

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2020 · $358,875

## Abstract

ABSTRACT
Alcohol-induced liver damage remains a major health issue. From the previous funding cycle, we determined
that mice with impaired signaling through the transforming growth factor β (TGF-β) pathway, that depends on
Smad3 and the Smad adaptor β2 spectrin (β2SP, Sptbn1) phenocopy Beckwith-Wiedemann Syndrome
(BWS). Interestingly, BWS is a human stem cell disorder that is associated with severe developmental
abnormalities and liver disease characterized by steatosis, chronic hepatitis, inflammation, and neoplasia.
TGF-β deficient mice (Sptbn1+/-, Sptbn1+/-Smad3+/-) had altered function of the chromatin organizing protein
CTCF (CCCTC-binding factor), a protein that we found also binds Smad3 and β2SP. These TGF-β mutant
mice also had reduced expression of FancD2, encoding a protein involved in DNA repair, and increased
expression of genes associated with stem cells, such as ALDH, encoding aldehyde dehydrogenase, and
TERT, encoding the catalytic subunit of telomerase. Moreover, the TGF-β mutant mice were deficient in repair
of DNA crosslinking damage. The TGF-β mutant mice are highly sensitive to the toxic effects of alcohol, and
develop liver cancers.
Therefore, we hypothesize that the inflammation and liver injury in the TGF-β deficient mice result from altered
impaired CTCF function that together with Smad3 and β2SP defect, impair expression of key genes involved in
DNA repair (FancD2) and stem cell homeostasis, and that these mice will be susceptible to alcohol-induced
liver inflammation, injury, and cancer. To explore these hypotheses, we will test mechanisms by which the
tripartite complex of CTCF, Smad3 and β2SP regulates FancD2 expression, stem cell homeostasis in the liver,
and the response to alcohol-induced liver injury.
To explore roles for FancD2 in stem cell homeostasis, we will investigate the relationship between this TGF-β
pathway and FancD2 in liver cells positive for the stem cell marker CD133 (also known as Prom1) from our
TGF-β deficient mice (Sptbn1+/-, Sptbn1+/-Smad3+/-), as well as in vivo studies with our mice that have already
been engineered to have inducible impairment of the pathway. This application will enable studies that provide
new understanding into stem cell-driven responses to alcohol in the liver, which will provide insights into
treating various types of not only alcohol-induced liver injury but liver diseases associated with inflammatory
responses.

## Key facts

- **NIH application ID:** 9898199
- **Project number:** 5R01AA023146-15
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Lopa Mishra
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $358,875
- **Award type:** 5
- **Project period:** 2004-04-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898199

## Citation

> US National Institutes of Health, RePORTER application 9898199, Role of Beta Spectrin and Smad in Alcohol Induced Liver and GI Cell Proliferation (5R01AA023146-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898199. Licensed CC0.

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