# Regulation of Tendon Enthesis Development and Healing via HIF1

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $533,063

## Abstract

ABSTRACT
 Achilles tendon ruptures are common musculoskeletal injuries, and the rate of rupture is rising with
increased participation in sports. Vascular irregularities and degenerative changes to extracellular matrix
(ECM) result in poor biomechanical properties that increase risk of tendon rupture. We have discovered that,
following Achilles tendon rupture in mice, the tendon-bone enthesis exhibits profound cell loss, which impairs
remodeling and further increases susceptibility to degeneration. This focal cell loss within the enthesis
motivated our work to study enthesis cell survival during growth and following tendon injury. Our preliminary
studies in mice have established the Achilles enthesis maintains a hypoxic niche during perinatal growth and
depends on Hypoxia Inducible Factor-1a (HIF1a) for enthesis cell survival. Targeted loss of Hif1a in tendon
and enthesis progenitor cells leads to focal cell death, disruption of enthesis ECM, and failed integration of
tendon into bone. Conversely, overexpression of Hif1a rescues cell within the enthesis following Achilles
tendon injury, suggesting its potential role in guiding tendon and enthesis regeneration. Therefore, we
hypothesize hypoxia is critical for establishing the enthesis progenitor cell/ECM niche, and cell survival in this
niche depends on and is enhanced by Hif1a. Our central goal is to define HIF1-dependent mechanisms of cell
function and ECM production during growth and repair of the fibrocartilage enthesis. We hypothesize that
HIF1a drives enthesis cell differentiation in part by regulating cell survival and ECM deposition. We will use
innovative approaches (e.g., in vivo reporters; subcellular spatial RNA-sequencing; synthetic hydrogels;
nascent protein labeling) to establish the role of HIF1a and hypoxia in maintaining, establishing, and protecting
enthesis progenitors. Our long-term goal is to develop druggable therapeutics to prevent Achilles tendon
rupture and improve tendon and enthesis healing. In Aim 1, we will establish the time course of progenitor cell
survival, differentiation, and ECM deposition in the mouse Achilles enthesis using inducible and tissue-specific
Hif1a-loss and gain of function models. Additionally, we will use synthetic 3D hydrogels to study the effects of
HIF1a and hypoxia on tendon/enthesis progenitor cell survival, nascent ECM deposition, and
mechanotransduction. In Aim 2, we will use parallel approaches to determine if and how HIF1a contributes to
functional healing of Achilles tendon and enthesis using inducible HIF1a LOF and GOF mice with HIF (HIF1a-
GFP and HIF2a-mCherry) reporters and structural/functional testing. We will also use novel HIF-targeting
drugs to determine the therapeutic potential of HIF-agonists in tendon and enthesis healing. Together, we will
identify the emergent role of HIF1a and hypoxia during tendon and enthesis development and repair following
injury. Ultimately, this work will establish the potential therapeutic role o...

## Key facts

- **NIH application ID:** 10797725
- **Project number:** 1R01AR082348-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Megan L. Killian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $533,063
- **Award type:** 1
- **Project period:** 2024-03-26 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10797725

## Citation

> US National Institutes of Health, RePORTER application 10797725, Regulation of Tendon Enthesis Development and Healing via HIF1 (1R01AR082348-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10797725. Licensed CC0.

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