# Regulatory cascades in gastrointestinal proliferation

> **NIH NIH R37** · UNIVERSITY OF PENNSYLVANIA · 2020 · $396,415

## Abstract

The intestinal epithelium is one of the most rapidly renewing tissues in the body, and thus the ideal tissue to
study somatic stem and progenitor cell biology. The small intestinal epithelium is composed of a single layer
of cells that contains four major differentiated cell types as well as intestinal stem cells (ISCs) and progenitor
or transit amplifying cells that replenish differentiated cells throughout life. While the past twenty years have
seen great progress in our understanding of the signaling pathways and transcriptional regulators that
control intestinal proliferation and differentiation, our understanding of the epigenetic factors that control
these important processes is rather limited. Equally important is the identification of the intestinal stem cell
niche, and the characterization of its function in molecular detail. To address this knowledge gap, I propose
the following Specific Aims:
In specific Aim 1, we will determine if Foxl1+ subepithelial telocytes are required for providing critical Wnt
signals during gastrointestinal development and in R-spondin free enteroid culture. We will employ our
newly developed genetic and molecular tools to determine the signaling pathways controlled by telocytes
during intestinal development using mouse models. In Aim 2, we will investigate the contribution of
polycomb complex mediated gene repression via histone H3K27 trimethylation on intestinal stem cell
biology and regeneration. To this end, we will employ tissue and cell type specific gene ablation of two
genes encoding critical H3K27me3 demethylases in the intestinal epithelium, both under homeostatic
conditions and after ablation of Lgr5 stem cells.
RELEVANCE (See instructions):
Gastrointestinal cancer is a significant health problem, ranking fourth in incidence and second in death
among cancers in the United States. Abnormal differentiation and increased proliferation of the intestinal
epithelium are hallmarks of carcinogenesis. The molecular mechanisms that regulate cellular proliferation
and differentiation in gastrointestinal development are far from being understood completely. Therefore, we
will analyze the impact of the intestinal stem cell niche cells on intestinal growth and function, and test the
contribution of histone demethylation to intestinal health.

## Key facts

- **NIH application ID:** 9995456
- **Project number:** 5R37DK053839-23
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** KLAUS H KAESTNER
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,415
- **Award type:** 5
- **Project period:** 2017-08-20 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9995456

## Citation

> US National Institutes of Health, RePORTER application 9995456, Regulatory cascades in gastrointestinal proliferation (5R37DK053839-23). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9995456. Licensed CC0.

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