Armando Villalta, PhD – UCI ICTS Institute for Clinical and Translational Science

Armando Villalta, PhD

Physiology and Biophysics

Mentor: Tahseen Mozaffar

Project Title: A novel CD52+ macrophage population that impairs skeletal muscle regeneration

The long-term goal of my research is to define the biological basis for immunological differences that exist among muscle disorders, and to develop a platform for the discovery of new therapeutic targets and biomarkers for muscle disease. Duchenne muscular dystrophy (DMD) and sporadic inclusion body myositis (sIBM) are incurable muscle diseases that severely impair quality of life and lead to early death. DMD is a childhood, X-linked muscle disorder caused by mutations in the dystrophin gene1,2, affecting ~1:5,000 boys worldwide3,4. In contrast, sIBM is a late-onset muscle disease of unknown etiology, affecting ~1:35,000 individuals over the age of 455. Although the etiologies of these muscle disorders differ, both encompass the immune system as major determinants of disease pathogenesis. Myeloid cells, including macrophages, infiltrate DMD and sIBM muscle, and contribute differently to the pathogenesis of each disorder through mechanism that are not well-defined6,7. This gap in knowledge prevents the field from fully understanding the role of the immune system in muscle disease, and discovering new therapeutic strategies for these disorders. Single-cell RNA sequencing (scRNA-seq) represents a powerful method for defining the mechanism of immune cell- mediated contributions to muscle disease by determining transcriptional networks that underlie the phenotypic and functional characteristics of immune cells in diseased muscle. Since the last submission of my KL-2 application, my laboratory used scRNA-seq to characterize muscle macrophages in a mouse model of DMD. The scRNA-seq analysis identified a novel CD52+ macrophage population that expressed high levels of IL-1b and was expanded in diseased muscle. Previous studies have shown that IL-1b impairs muscle stem cell differentiation and is induced in human muscle disorders8,9. The objective of my proposed study is to define the regulation of CD52+ macrophages in human with muscle disease and determine their function through in vitro assays. Specifically, I will test the hypothesis that CD52+ macrophages are expanded in DMD and sIBM patients and the extent of expansion correlates with disease severity. I further hypothesize that CD52+ macrophages impair muscle stem cell differentiation in IL-1b-dependent manner. The rationale for using DMD and sIBM as comparative study groups stems from the clinical observation that immunosuppressive glucocorticoids significantly delay the progression of DMD, but are not efficacious in sIBM. Thus, studies defining differences in the immune response in these diseases will provide valuable insight to understand the unresponsiveness to glucocorticoids in some muscle disorders. By defining such differences my study promises to identify unique immunological parameters that may predict disease severity, and novel therapeutic targets for the design of transformative treatments for muscle disease like sIBM.