# Dissecting the Molecular Mechanisms that Govern Notch Mediated Skeletal Stem Cell Maintenance Throughout Adulthood/Aging.

> **NIH NIH F30** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $29,471

## Abstract

PROJECT SUMMARY
Orthopedic injuries represent one of the most significant health and economic burdens in our nation. Bone
fragility with age due to diseases such as osteoporosis increases the risk for fracture, while at the same time
leading to delayed bone healing resulting in a higher risk for non-union. With a growing aging population, the
demand for therapeutics to combat age-related bone loss is one of the pillars of the American Orthopedic
Association’s “Own-the-Bone” initiative. Current treatments mainly focus on preventing further bone loss rather
than increasing bone mass in a substantial manner. Skeletal stem and progenitor cells (SSPCs) are essential
for proper bone mass and bone healing. SSPCs are known to decline in frequency and function with age.
Therefore, SSPCs represent the most direct target to increase bone mass. Previous studies and our own data
suggest that Notch signaling plays a pivotal role in SSPC homeostasis and self-renewal. We recently identified
a conditional Notch knockout mouse model which exhibits a striking phenotype of increasing bone formation in
all skeletal elements in aging mice. This mouse model, the Ncstnf/f;LepR-cre mouse, is deficient in Nicastrin
(Ncstn), an essential component of the Notch signal transduction machinery of all 4 Notch receptors in LepR+
SSPCs. This model has exciting therapeutic potential to combat age-related bone loss. Based on this cKO model
and our preliminary data I hypothesize that Notch signaling is essential in maintenance of the skeletogenic stem
cell pool during adulthood and aging. In order to investigate the molecular mechanism by which Notch signal
inhibition leads to increased trabecular bone mass with age, we performed bulk RNA sequencing on LepR+
SSPCs from middle-aged WT and cKO mice. This unbiased sequencing approach identified Ebf3 as a
significantly downregulated gene in cKO cells and therefore potential downstream mediator of Notch signaling
in promoting SSPC differentiation into osteoblasts. Previous work has linked Ebf3 to the inhibition of
osteogenesis, however, the upstream regulators of Ebf3 are not yet known. Also, while others have looked into
the role of Notch in SSPCs, the downstream mechanisms by which Notch is controlling SSPC function are still
largely unknown. Therefore, this proposal aims to i) define the precise role of Notch signaling in SSPCs during
aging/adulthood on proliferation, self-renewal and differentiation and ii) uncover the molecular mechanism by
which Notch signaling is having the effects on proliferation, self-renewal and differentiation. These aims will
provide novel specific mechanistic insights into the mechanism by which a Notch-Ebf3 signaling axis maintains
skeletal stem cells in their primitive state throughout the lifespan of an animal.

## Key facts

- **NIH application ID:** 10783771
- **Project number:** 5F30AG072834-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Lindsey Hope Remark
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $29,471
- **Award type:** 5
- **Project period:** 2022-02-28 → 2024-05-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10783771

## Citation

> US National Institutes of Health, RePORTER application 10783771, Dissecting the Molecular Mechanisms that Govern Notch Mediated Skeletal Stem Cell Maintenance Throughout Adulthood/Aging. (5F30AG072834-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10783771. Licensed CC0.

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