# Gut cell plasticity during diabetes treatment

> **NIH NIH K01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $87,301

## Abstract

Project Summary
There is irreversible destruction of insulin-secreting pancreatic β-cells during type 1 diabetes. Consequently,
individuals with this disease are dependent on continual insulin injections to manage their diabetes which is
burdensome to patients. However, if one could trigger a patient's own cells to generate endogenous insulin it
would essential cure these individuals of their diabetes. Elimination of the transcription factor Foxo1 in a
population of intestinal endocrine progenitor (Neurogenin3+) cells prompts them to secrete functional insulin and
reverse diabetes in mice. Interestingly, there are also more Ngn3+ cells in the intestines of these mice. Using a
reporter mouse, the candidate has found that Foxo1 is expressed in Ngn3+ and some acid-secreting parietal
cells in the stomach epithelium. While ablation of Foxo1 in both of these cell populations triggers the appearance
of insulin immune-reactive cells, it also increases Ngn3 expression and parietal cell numbers. The candidate
hypothesizes that elimination of Foxo1 in the stomach changes the cell plasticity of this organ. To further
understand this process, using three specific aims, this research proposal will 1) study specific changes
to gastric enteroendocrine and parietal cells when Foxo1 is deleted in mice and in human cells and 2)
define molecular pathways important to insulin-cell conversion. To accomplish this, Foxo1 will be
abolished, using cre recombinase technology, in primary stomach cultures (Aim1.1), in two separate populations
of cells in mice (Aim1.2), and in human induced pluripotent cells (iPSC) (Aim2). Changes to cell type, distribution,
proliferation, and death will be measured using immunohistochemistry and qPCR. Important to career
development, new research skills (iPSC culture and genome modification by CRISPR) will be learned in Aim2 of
this proposal. Using FACs to isolate cells, Aim3 will analyze Foxo1-deleted primary stomach cells and stomach
insulin+ cells using RNA-seq. Unique multi-color fluorescent reporters will be used in both Aim2 and Aim3. Taken
together, the proposed experiments will likely reveal new molecular targets/pathways important in the conversion
of stomach cells to those that produce insulin, ultimately to discover a new avenue of treatment for type 1
diabetes. These experiments are complimented by a career development plan in which the candidate will
learn new research techniques, broaden her scientific network through attending conferences, and
develop her writing skills (through coursework, submitting manuscripts/R01 application) so that she is
poised to become an independent investigator. Both the career development plan and research proposal will
be completed at Columbia University, a prestigious institution.

## Key facts

- **NIH application ID:** 10668593
- **Project number:** 3K01DK121873-04S1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Wendy Marie McKimpson
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $87,301
- **Award type:** 3
- **Project period:** 2019-07-01 → 2024-12-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10668593

## Citation

> US National Institutes of Health, RePORTER application 10668593, Gut cell plasticity during diabetes treatment (3K01DK121873-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10668593. Licensed CC0.

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