Conrad C Weihl
Washington University in St Louis, MO·Medicine & Clinical Research·Early-career
Muscle weakness that comes on through inherited mutations or later in life can take away walking, swallowing and breathing, and most forms have no treatment. Two threads of work connect here.
- Fields
Medicine & Clinical Research
Neuroscience
Genetics
- Topics
inclusion body myopathy
myofibrillar myopathy
limb-girdle muscular dystrophy
- Grants
- 2 known grants, through Mar 2029
What they work on
- Resolve variants of unknown significance in limb-girdle muscular dystrophy (LGMD) genes, DNA changes whose disease relevance is unclear, by developing assays of pathogenicity using patients and samples from an existing neuromuscular biorepository.
- Perform natural history studies of rare muscle diseases, defining the phenotypic spectrum and how symptoms progress, by following patients enrolled in the Washington University Neuromuscular Genetics Project.
- Confirm that proteopathic seeds derived from patient muscle can induce aggregation of TDP-43, an RNA-binding protein found in inclusion body myopathy inclusions, in recipient muscle fibers.
- Demonstrate that TDP-43 and desmin aggregates permeabilize lysosomal membranes, the cell's degradation compartments, and that this causes failure of autophagy and lysosomal signaling in muscle.
- Evaluate whether protein aggregates propagate from one myofiber to a neighboring myofiber, testing a prion-like mechanism of spread as the link between inclusions and rimmed vacuoles in inclusion body myopathy.
- Train graduate students, resident physicians, neuromuscular fellows and junior faculty in translational myology by integrating them into the existing clinical and laboratory research infrastructure.
More about the research
One is clinical: pinning down which genetic variants in patients actually cause disease, and charting how rare muscle diseases progress over time. The other is mechanistic: asking how clumps of misfolded protein inside muscle fibers damage the cell's recycling machinery and whether those clumps spread from fiber to fiber.
Why it matters
Inherited and acquired muscle weakness causes major disability and shortened life, and roughly half of patients tested for inherited myopathy receive an uninformative result because their genetic variant cannot be interpreted. Tools to classify these variants, plus natural history data, would give families clearer diagnoses and supply the outcome measures that clinical trials in rare muscle diseases require. For inclusion body myopathy, which has no treatment, showing that protein aggregates spread between muscle fibers would identify stopping that spread as a therapeutic target.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
John Buchan
University of Arizona, AZ·Biochemistry
Define how much each reported clearance route contributes to removing stress granules and P-bodies under disease-relevant stress, and how the routes cooperate. Use genetic, biochemical and cell biology assays in yeast and human cells.
Rita Perlingeiro
University of Minnesota, MN·Biomedical Engineering
Determine how the host muscle environment affects engraftment of PSC-derived myogenic progenitors in an immune-deficient FKRP mutant mouse model of dystroglycanopathy.
Darko Bosnakovski
University of Minnesota, MN·Genetics
Test whether transient DUX4 expression in the inducible iDUX4pA;HSA mouse model causes lasting changes in muscle physiology and histology (tissue structure) after the gene is switched off.
The school
Washington University in St Louis: 97 labs on PI Pages, $1.2B a year on research, 365 research doctorates a year.
Reach out
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