The candidate is an MD/PhD trained clinical neurologist with a career goal to investigate the cellular mechanisms of aging in relation to skeletal muscle disorders, using inclusion body myositis (IBM) as a prototypical disease. The mentored scientific training will be performed jointly in the labs of Drs. Alan Pestronk and Phyllis Hanson. The merger of these two diverse scientists fosters an environment that will allow the candidate to become an independent investigator. IBM and hereditary inclusion body myopathy (HIBM) affect aged patients, cause significant morbidity and mortality and have no effective treatment. Missense mutations in p97/VCP cause the autosomal dominantly syndrome HIBM, Paget's Disease and frontotemporal dementia (IBMPFD). P97/VCP is a AAA ATPase (ATPase Associated with other cellular Activities) and has a clear role in protein degradation, in particular the ubiquitin-proteasome pathway. The central hypotheses to be tested during the proposed project are the following: 1) IBMPFD mutations in p97/VCP cause the protein to aggregate;2) IBMPFD mutant p97/VCP aggregates affect the degradation of cellular proteins and are responsible for the characteristic histopathology of cytoplasmic, ubiquitin positive inclusions seen in IBM and HIBM diseased muscle;3) An understanding of the molecular mechanism of HIBM will elucidate the pathogenesis of IBM and other aging related diseases. The candidate will test these hypotheses using the following experimental designs: 1) Purified recombinant p97/VCP protein to evaluate structure and enzyme activity;2) Cultured myoblasts expressing p97/VCP proteins to evaluate cellular degradative pathways and the proteins affected;and 3) Transgenic mice expressing familial mutant p97/VCP-R155H to model the pathologic and clinical aspects of HIBM. These studies will lend insight into the molecular and cellular mechanisms involved in IBM disease pathogenesis and are critical for identifying future therapeutic targets.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Clinical Investigator Award (CIA) (K08)
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Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Williams, John
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Washington University
Schools of Medicine
Saint Louis
United States
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Weihl, C C (2011) Valosin containing protein associated fronto-temporal lobar degeneration: clinical presentation, pathologic features and pathogenesis. Curr Alzheimer Res 8:252-60
Andley, Usha P; Hamilton, Paul D; Ravi, Nathan et al. (2011) A knock-in mouse model for the R120G mutation of *B-crystallin recapitulates human hereditary myopathy and cataracts. PLoS One 6:e17671
Weihl, Conrad C; Miller, Sara E; Zaidman, Craig M et al. (2011) Novel GNE mutations in two phenotypically distinct HIBM2 patients. Neuromuscul Disord 21:102-5
Ritz, Danilo; Vuk, Maja; Kirchner, Philipp et al. (2011) Endolysosomal sorting of ubiquitylated caveolin-1 is regulated by VCP and UBXD1 and impaired by VCP disease mutations. Nat Cell Biol 13:1116-23
Fuentealba, Rodrigo A; Udan, Maria; Bell, Shaughn et al. (2010) Interaction with polyglutamine aggregates reveals a Q/N-rich domain in TDP-43. J Biol Chem 285:26304-14
Ju, Jeong-Sun; Varadhachary, Arun S; Miller, Sara E et al. (2010) Quantitation of ""autophagic flux"" in mature skeletal muscle. Autophagy 6:929-35
Weihl, Conrad C; Pestronk, Alan (2010) Sporadic inclusion body myositis: possible pathogenesis inferred from biomarkers. Curr Opin Neurol 23:482-8
Ju, Jeong-Sun; Weihl, Conrad C (2010) Inclusion body myopathy, Paget's disease of the bone and fronto-temporal dementia: a disorder of autophagy. Hum Mol Genet 19:R38-45
Gurnett, Christina A; Desruisseau, David M; McCall, Kevin et al. (2010) Myosin binding protein C1: a novel gene for autosomal dominant distal arthrogryposis type 1. Hum Mol Genet 19:1165-73
Varadhachary, Arun S; Weihl, Conrad C; Pestronk, Alan (2010) Mitochondrial pathology in immune and inflammatory myopathies. Curr Opin Rheumatol 22:651-7

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