Project Details
Description
Project Summary
Duchenne muscular dystrophy (DMD), the most common genetic muscle disease, is lethal with no cure at this
point. Muscle pathology of DMD and its mouse model mdx5cv features chronic inflammation with predominant
macrophage (MP) infiltration. Preclinical studies by our lab and others demonstrate that ameliorating muscle
inflammation improves muscular dystrophy phenotype. It also improves local tissue environment to promote
muscle regeneration and gene and cell engraftment. Tissue macrophages are functionally heterogeneous with
diverse origins. They can be pro-inflammatory, pro-fibrotic, or pro-regenerative depending on the tissue
environment and origins. While tissue inflammatory MPs are derived from blood monocytes (MOs), tissue
resident MPs can originate from blood MOs and/or embryo. Murine peripheral blood MOs consist of two
subsets, Ly6Chi and Ly6Clo cells, with corresponding subsets in humans. Ly6Chi cells (CCR2+/CX3CR1low) are
inflammatory MOs, which enter tissues in response to injury via CC chemokine receptor 2 (CCR2) and then
differentiate into inflammatory MPs. Within injured tissues, Ly6Chi MPs can switch into Ly6Clo MPs. Ly6Chi MOs
may also contribute to tissue resident MPs at the steady state. Ly6Clo MOs (CCR2-/CX3CR1hi) patrol the
vascular endothelial surface and may enter normal tissue via chemokine receptor CX3CR1 to replenish
resident MPs. Embryo-derived tissue resident MPs are also Ly6Clo, and they persist into adult tissues through
proliferative self-renewal. Our preliminary data show that both Ly6Chi and Ly6Clo subsets of MPs accumulate in
mdx5cv skeletal muscle, and that CCR2 is essential to the muscle recruitment of Ly6Chi inflammatory MOs.
Knockout of CCR2 diminishes intramuscular Ly6Chi MPs at all stages, but it only reduces Ly6Clo MPs at early
stages. The reduction of intramuscular MPs at the early stages is accompanied by decreased muscle damage,
reduced muscle fibrosis, and improved muscle function, which supports a pathogenic role for the intramuscular
Ly6Chi MPs. However, the beneficial effects are lost at the late stage in the mdx5cv/Ccr2-/- mice after the
expansion of intramuscular Ly6Clo MPs. Targeting Ly6Chi MP alone does not provide sustained benefits. We
thus generate our central hypothesis that Ly6Clo MPs also play a pathogenic role in the mdx5cv diaphragm
dystrophy, Ly6Clo MPs from different origins may contribute differently, and targeting the monocytic origins is
therapeutically useful. We will test our hypothesis by three Specific Aims. Aim 1 will study the origins of
skeletal muscle resident MPs at the normal steady state. Aim 2 will define the origins of intramuscular MPs in
the mdx5cv diaphragm. Aim 3 will determine the effector and regulatory functions of intramuscular MPs derived
from different origins in the mdx5cv diaphragm, and test the therapeutic potential of targeting monocytic origins.
This project will address the key questions related to the intramuscular MPs, and the knowledge gained will be
critical to the future development of novel monocyte/macrophage-based therapies for DMD.
Status | Active |
---|---|
Effective start/end date | 5/08/19 → 30/06/23 |
Funding
- National Institute of Arthritis and Musculoskeletal and Skin Diseases: $351,378.00
- National Institute of Arthritis and Musculoskeletal and Skin Diseases: $372,411.00
- National Institute of Arthritis and Musculoskeletal and Skin Diseases: $368,248.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.