Basic Science
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Treg-mediated regulation of macrophage activation and function during muscular dystrophy
The objective of this study is to define how regulatory T cells (Treg) regulate macrophage-stromal interactions in muscle, and how these interactions can be therapeutically manipulated to alter disease progression. In preliminary studies we used single-cell RNA sequencing (scRNAseq) to characterize macrophages in healthy and dystrophic muscle, and found a novel galectin-3+/spp1+ macrophage population. Given the role of galectin-3 and spp1 in fibrosis, we are currently performing studies to test the hypothesis that galectin-3+ macrophages promote muscle fibrosis by promoting the fibrogenic differentiation of stromal progenitors.
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Tolerization of dystrophin and adeno-associated virus immunity
Adeno-associated virus (AAV) micro-dystrophin (dys) gene therapy shows great promise to cure Duchenne muscular dystrophy (DMD). We are conducting several multi-disciplinary studies to determine if AAV- and dystrophin-specific immune responses impede on the success of gene therapy, and determine if regulatory T cells (Tregs) mitigate these immune responses in the mdx mouse model of DMD. We are using adjuvant-based immunization methods to induce dystrophin- and AAV-specific T cells, and functional studies to determine if dystrophin- and/or AAV-specific T cells impair muscle function following AAV-dys gene therapy.
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Innate lymphoid cells regulation of muscle regeneration and fibrosis
We recently made the discovery that innate lymphoid cells (ILC1 and ILC2) are activated by muscle injury and are elevated in dystrophic muscle. We have several genetic mouse models in which ILC1s and ILC2s have been depleted from dystrophic mice. In preliminary studies, we found that stromal progenitors express IL-33 to potently activate ILC2s and the expression of genes associated with fibrosis, suggesting that ILC2s promote muscle fibrosis during muscular dystrophy.
