# Cell adhesion-dependent mechanisms of beta cell growth and homeostasis

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2022 · $137,494

## Abstract

SUMMARY
 Our laboratory has recently discovered that αE-catenin, a regulator of cell adhesion processes, play a
critical role in the development of the islet cell lineage by virtue of its function as a repressor of the Sonic
Hedgehog (SHH) pathway. We found that deletion of αE-catenin in Pdx1+ multipotent pancreatic progenitors
results in the accumulation of immature bipotent Sox9+ progenitors. These αE-cateninnull/Sox9+ progenitors are
unable to adopt an endocrine cell phenotype due to a constitutive activation of the SHH pathway. Interestingly,
pharmacological blockade of the SHH pathway in these αE-cateninnull/Sox9+ progenitors restored their ability to
differentiate into hormone expressing islet cells. More recently, we found that the temporal downregulation of
αE-catenin by siRNA in human adult islets can elicit significant β-cell replication. Hence, based on these
results, and on the notion that αE-catenin can also block Wnt signaling, we hypothesize that in differentiated
islet cells αE-catenin may represent yet another “brake” on cell cycle entry by virtue of its opposing functions
on signaling SHH and Wnt pathways that would normally promote cell proliferation.
 To test this hypothesis, we will focus our studies on the following Specific Aims:
 Aim 1: Determine the role of αE-catenin as a modulator of β-cell growth during embryonic development and
in postnatal life, under physiologic conditions and in injury settings. In these experiments will also test if the
conditional deletion of αE-catenin in embryonic and in postnatal β-cells will de-repress SHH and Wnt, which in
turn are expected to elicit cell cycle entry. In parallel studies we will also test if the conditional ablation of αE-
catenin in postnatal life will enhance β-cell regeneration in the streptozotocin model of β-cell injury, and/or in
response to metabolic stressors such as exposure to high fat diet.
 Aim 2: Targeting αE-catenin-dependent signaling axis for the ex vivo expansion of human islet cells and for
the reprogramming of ductal cell populations, both in vitro and in vivo in cell transplantation models. Based on
the notion that human islet cells exhibit a modest propensity to respond to pro-growth stimuli, these studies will
test if knocking down αE-catenin in human adult β-cells will de-repress SHH and Wnt, and foster cell
proliferation. A similar strategy will be tested on human adult ductal tissue, usually discarded from islet isolation
procedures, to test if they can regain an embryonic-like competency to differentiate into endocrine cells, both in
vitro and in vivo in cell transplantation models.
 Collectively, our strategy to transiently down-regulate αE-catenin expression, allowing for the de-repression
of the SHH pathway may prove as a powerful strategy to promote the ex vivo expansion of β-cells, and/or re-
direct the differentiation competency of adult ductal cells toward a β-cell phenotype. Hence, we anticipate that
these studies harbor significant translat...

## Key facts

- **NIH application ID:** 10528306
- **Project number:** 3R01DK121275-03S1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** VINCENZINO CIRULLI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $137,494
- **Award type:** 3
- **Project period:** 2020-04-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10528306

## Citation

> US National Institutes of Health, RePORTER application 10528306, Cell adhesion-dependent mechanisms of beta cell growth and homeostasis (3R01DK121275-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10528306. Licensed CC0.

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