# Notch function in postnatal intestinal and mesenteric lymphatics

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $400,000

## Abstract

PROJECT SUMMARY/ABSTRACT
The intestinal lymphatic system serves physiological functions, including uptake of lipids, vitamins, immune
surveillance, and fluid homeostasis. It is made up of distinct lymphatic endothelial cell populations that
require regulatory pathways to maintain lymphatic vessel fate, microenvironment and functionality. We have
demonstrated that Notch functions in cell fate determination of lymphatic endothelial cells and to maintain
intestinal lymphatic homeostasis. Notch signaling is active throughout the intestinal lymphatic system,
including the ductal, valve, and lacteal lymphatic endothelium. Disrupting Notch signaling or Mmp14 leads
to shared lymphangiogenic and mesenteric lymphatic valve defects. Notch and MMP14 are linked to diverse
intestinal and cardiovascular disorders and our novel studies will shed light on their role in intestinal
diseases that have lymphatic defects as an underlying factor. We hypothesize that Notch regulates the
extracellular matrix of the intestinal and mesenteric lymphatic vasculature via induction of MMPs and
regulation of matrix proteins in a context-dependent manner. To address this hypothesis, we will determine
lymphatic endothelial Notch function in postnatal intestinal and mesenteric lymphatics. We will use
transgenic mice to transcriptional profile Notch responses in intestinal and mesenteric lymphatic endothelial
cells and in a tether-ligand assay. The mechanism by which Notch regulates Mmp14 expression and its
effects on lymphatic endothelial cell behavior will be determined. Conditional mice will be used to alter
lymphatic endothelial Notch signaling with and without lymphatic endothelial Mmp14 deletion to define
Notch functions in maturation and homeostasis of mesenteric lymphatic collecting ducts. As Notch is active
in lacteal endothelial cells and Notch mutants display lacteal defects, we will use conditional mouse models
to study the role of Notch in the lacteals during development and homeostasis. We will determine if
abnormal matrix accumulation in the villi in Antxr1-/-;Antxr2-/- mice leads to lymphatic dysfunction and
changes lymphatic endothelial Notch signaling. Our proposed research aims to uncover mechanisms by
which Notch modulates extracellular matrix proteins and regulatory pathways in lymphatic endothelial cells
to understand digest tract lymphatic development, homeostasis and function.

## Key facts

- **NIH application ID:** 10147048
- **Project number:** 5R01DK107633-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Carrie J Shawber
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $400,000
- **Award type:** 5
- **Project period:** 2017-05-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147048

## Citation

> US National Institutes of Health, RePORTER application 10147048, Notch function in postnatal intestinal and mesenteric lymphatics (5R01DK107633-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10147048. Licensed CC0.

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