Single cell gene expression atlas of dysferlin-deficient muscle

Jyoti Jaiswal, PhD and Pier Lorenzo Puri, MD

Center for Genetic Medicine, Children’s Research Institute, Washington DC and Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA

Dr. Jyoti Jaiswal is Professor of Genomics and Precision Medicine at the George Washington University School of Medicine and Senior Investigator at the Children’s National Hospital in Washington DC. Dr. Lorenzo Puri is a Professor at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.

Research Projects

Objective: 
Understand the identity of the cell type(s) implicated in the pathogenesis of dysferlinopathies and predict alterations of signaling pathways and functional interactions among these cell types that contribute to disease progression and muscle loss.

Dysferlinopathy involves an age-dependent decline in muscle function following onset of symptoms past adolescence. As the disease progresses it results in excessive muscle inflammation and replacement of muscle fibers by fatty deposits. Our recent studies using dysferlinopathic mouse model indicate that accumulation of fat in dysferlin-null muscle is caused by altered interactions among muscle-resident cell types. In particular, these studies have revealed a progressive accumulation of fibroadipogenic progenitors (FAPs) with an adipogenic phenotype, likely induced by altered cellular interactions of muscle resident cells in the dysferlin null mice. However, the exact nature and origin of these alterations have not been deciphered.

We propose to fill this gap by exploiting singe cell RNA sequencing to provide the transcriptional profiles of mononuclear cells (including muscle stem cells and other muscle resident cell types) from dysferlinopathic muscles at sequential stages of disease progression.

This collaborative study is aimed at utilizing the combined expertise of the team in muscle biology, dysferlinopathy, and RNA sequencing studies. This will be utilized to generate single cell gene expression datasets to obtain the fundamental understanding of the identity of the cell type(s) implicated in the pathogenesis of dysferlinopathies and predict alterations of signaling pathways and functional interactions among these cell types that contribute to disease progression and muscle loss. Comparison with healthy control mice, as well as with available datasets of from mouse models of other muscular dystrophies, will help define common, and disease-specific patterns of gene expression in dysferlinopathy. This will set the groundwork for future translation of these findings into mechanistic and patient studies to identify novel biomarkers of disease progression and targets for therapeutic interventions.