# Notch signaling and Bone Fracture Healing

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2023 · $560,953

## Abstract

There is an urgent clinical need to develop new therapeutics to promote healing of bone. While most
bone injuries heal, many do not, particularly large defects. Understanding cellular signaling mechanisms that
regulate normal healing, can lead us to new therapeutic targets. Notch signaling regulates the expansion and
differentiation of mesenchymal progenitor cells (MPC) and regulates vascularization of many tissues,
including bone. Our studies, and published studies from other investigators, show that Notch signaling is a
key regulatory pathway during bone healing. Indeed, our preliminary and published results show that
increasing Notch signaling in MPCs improves bone regeneration, and that global inhibition of Notch using
various models, deleteriously impacts healing. To sufficiently advance our understanding of Notch signaling
in bone healing, and translate these mechanistic observations, will require robust experimentation, including
preclinical studies in relevant injury models. Our long-term goal is to develop a clinically relevant approach
to increase Notch signaling that enhances bone healing.
 We hypothesize that Notch signaling promotes expansion of MPCs and callus vascularization, leading
to enhanced bone formation. We will interrogate the Notch signaling pathway during bone healing to reveal a
deeper understanding of ligands and receptors that are at play during healing, and the cell-type specific
expression of these signaling components. This work will be completed in two specific Aims, using state of
the art mouse models. In the first Aim, we will study the role of Notch ligands. Our work has previously
demonstrated that Jagged1 is the dominant Notch ligand expressed in MPCs and the osteochondrogenic
lineage. We will disrupt Jag1 specifically in MPCs, chondrocytes, osteoblasts and osteocytes in the callus
during fracture healing. Additionally, as Jag1 and Dll4 produced by endothelial cells regulate vascularization,
we will determine which is the dominant ligand regulating vascularization using conditional deletion of both
ligands from endothelial cells using Cdh5-CreER. A spectrum of fracture healing outcomes, including
vascularization, as well as effects on endothelial cell and MPC proliferation and MPC differentiation will be
determined in vivo. We will capitalize on our extensive experience using inducible Cre mice to ensure normal
development thereby by-passing developmental effects of ligand disruption. These studies will be
complemented with a translational study in which Jag1 protein, alone or in combination with an existing
therapy, BMP2, will be delivered during healing of critical sized femoral defects. In the second Aim, we will
examine the role of Notch receptors on MPC and endothelial cells using Notch1 or Notch2 floxed mice. We
will determine whether these receptors are critical for defect healing driven by BMP2 or Jag1. This study will
significantly advance the field by clarifying the cell-specific role of ligand and r...

## Key facts

- **NIH application ID:** 10589870
- **Project number:** 5R01AR055607-11
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Kurt David Hankenson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $560,953
- **Award type:** 5
- **Project period:** 2011-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10589870

## Citation

> US National Institutes of Health, RePORTER application 10589870, Notch signaling and Bone Fracture Healing (5R01AR055607-11). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10589870. Licensed CC0.

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