# Determining the Role of Spp1+ Macrophages in Muscle Regeneration in Peripheral Arterial Disease

> **NIH NIH K08** · DUKE UNIVERSITY · 2024 · $153,252

## Abstract

PROJECT SUMMARY
This proposal presents a three-year research career development program focused on elucidating the molecular
mechanisms and clinical significance of a pathologic macrophage population (Spp1+ macrophages) in peripheral
arterial disease (PAD). The candidate is a currently an Assistant Professor of Surgery in the Division of Vascular
& Endovascular Surgery at Duke University. He has clinical expertise in PAD and research experience in skeletal
muscle biology (CTSA KL2). He has now chosen to focus on the role immune system, particularly macrophages,
play in orchestrating skeletal muscle repair in PAD. Hence, he has sought additional training. The proposed
experiments and didactic work will provide the candidate with a unique skillset that will enable him to transition
to independence as a surgeon-scientist.
Novel therapies for limb loss remain an unmet need. The long-term goal of my research program is to elucidate
the molecular mechanisms of skeletal muscle regeneration in PAD and develop cellular therapies for limb
preservation. Preliminary work in my lab has identified Spp1+ macrophages (Spp1+MΦ) as a pro-inflammatory
macrophage population that is associated with failed muscle regeneration in PAD patients. The overall objectives
of this proposal are to determine the mechanisms and clinical significance of Spp1+MΦ in PAD. The central
hypothesis is that Spp1+MΦ inhibit muscle regeneration by inhibiting muscle stem cell (MuSC) and macrophage
reparative programs. The rationale for this project is that determining the processes that regulate macrophage-
mediated tissue repair and establishing a link between macrophage phenotype and clinical outcomes will provide
a strong foundation for the development of immune-based therapies for PAD. The hypothesis will be tested by
pursuing three specific aims: 1) Determine if Spp1+MΦ inhibit MuSC regeneration in the ischemic limb; 2)
Determine if Spp1+MΦ inhibit macrophage polarization to a regenerative phenotype in the ischemic limb; and 3)
Determine if Spp1+MΦ are positively correlated with myopathy, limb loss and mortality in human PAD patients.
In Aims 1 and 2, we will perform hind limb ischemia on mice with conditional overexpression or ablation of Spp1
in myeloid cells. We will assess muscle regeneration and macrophage polarization via histologic,
immunofluorescence (IF), and transcriptional analysis. In Aim 3, we will leverage our large institutional PAD
tissue repository and use spatial transcriptomics and IF analysis to link Spp1+MΦ with dystrophic muscle and
adverse clinical outcomes, such as major amputation and mortality. The research proposed in this application is
innovative because it represents a dramatic paradigm shift in the scientific approach to PAD. This proposal
places the investigative spotlight on the interplay between the immune system and skeletal muscle repair in
PAD. The proposed research is significant because it is expected to provide a strong scientific justification f...

## Key facts

- **NIH application ID:** 10984305
- **Project number:** 1K08HL171949-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Kevin William Southerland
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $153,252
- **Award type:** 1
- **Project period:** 2024-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10984305

## Citation

> US National Institutes of Health, RePORTER application 10984305, Determining the Role of Spp1+ Macrophages in Muscle Regeneration in Peripheral Arterial Disease (1K08HL171949-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10984305. Licensed CC0.

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