A.) IBM Overview
Sporadic inclusion body myositis (IBM) is the most common acquired muscle
disease in adults over the age of 50, yet the underlying cause of the
disease is unknown, and there are no disease-modifying therapies. The
robust endomysial inflammation with autoreactive CD8+ T-cells invading
healthy-appearing myofibers in addition to an increased association of IBM
with specific HLA haplotypes and other autoimmune diseases suggests that
IBM is primarily an autoimmune disease. However, an association with aging,
lack of response to immunotherapy, and presence of pathological features
such as TDP-43 cytoplasmic aggregation seen in neurodegenerative diseases
suggest the immune response may be secondary to myodegeneration. Thus,
the relationship between inflammation, inclusions, TDP-43 pathology, and
degeneration in IBM is poorly understood.
B.) Using a Xenograft model to study the pathogenesis of Inclusion
The mechanisms underlying the pathogenesis of Inclusion Body Myositis
(IBM) have long eluded researchers. Part of this difficultly arises from
the unique combination of both inflammatory and degenerative features
observed within the muscle of patients. To better understand the roles these features play in
the development of IBM, our lab has developed a xenograft model of IBM.
The aims of this project are:
- To characterize a novel mouse xenograft model of sporadic IBM.
We’ve found that IBM muscle regenerates robustly in immunocompromised
host mice and recapitulates several features of the human pathology.
- To determine whether splicing repression is a major role of
TDP-43 in skeletal muscle.
Like many neurodegenerative diseases, IBM has been classified as
a TDP-43 proteinopathy characterized by nuclear clearing and
cytoplasmic aggregation of the RNA-binding protein TDP-43. We aim
to test whether this mislocalization of TDP-43 underlies muscle
degeneration in IBM.
- To test novel therapeutic targets in a xenograft model of IBM.
There are no clinically effective treatments for patients
diagnosed with IBM, and the lack of animal models for this
disease has been a fundamental obstacle for the development of
therapies. We hypothesize that this xenograft model will allow
us to carry out preclinical testing of potential therapeutics.
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