The applicant is a physician-scientist with an interest in age associated muscle disorders. This award will free him from clinical duties, allow him to focus on research and become a leader in the field. One age associated muscle disorder is due to mutations in valosin containing protein (VCP) which causes IBMPFD or inclusion body myopathy (IBM) associated with Paget's disease of the bone (PDB) and fronto-temporal dementia (FTD). Muscle weakness is the most prevalent phenotypic feature. Although IBMPFD itself is rare, each component (IBM, PDB and FTD) is exceedingly common in the general population. VCP mutations disrupt autophagosome maturation resulting in dysfunctional autophagy and muscle weakness. We propose to evaluate 1) Autophagosome maturation in skeletal muscle;2) Characterize a novel VCP complex necessary for the autophagic degradation of ubiquitinated proteins. 3) Evaluate the role of VCP and its cofactors on autophagosome maturation. The applicant will learn new techniques, forge new collaborations and develop a research program in his lab to understand the interplay between protein degradation pathways in age muscle disease. The K02 award mechanism will allow the applicant to focus full time on research and become a leader in the field.

Public Health Relevance

Pathologic protein inclusions accumulate in many divergent disease states associated with aging like inclusion body myositis and dementia. We hypothesis that an impairment in autophagy conferred by mutations in the protein VCP result in inclusion body myopathy associated with paget's disease of the bone and fronto-temporal dementia (IBMPFD). Understanding IBMPFD will lend insight into the treatment of other more common age related disorders.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Scientist Development Award - Research (K02)
Project #
Application #
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Velazquez, Jose M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Meyer, Hemmo; Weihl, Conrad C (2014) The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis. J Cell Sci 127:3877-83
Chou, Tsui-Fen; Bulfer, Stacie L; Weihl, Conrad C et al. (2014) Specific inhibition of p97/VCP ATPase and kinetic analysis demonstrate interaction between D1 and D2 ATPase domains. J Mol Biol 426:2886-99
Stein, Kevin C; Bengoechea, Rocio; Harms, Matthew B et al. (2014) Myopathy-causing mutations in an HSP40 chaperone disrupt processing of specific client conformers. J Biol Chem 289:21120-30
Gonzalez, Michael A; Feely, Shawna M; Speziani, Fiorella et al. (2014) A novel mutation in VCP causes Charcot-Marie-Tooth Type 2 disease. Brain 137:2897-902
Bibee, Kristin P; Cheng, Ya-Jian; Ching, James K et al. (2014) Rapamycin nanoparticles target defective autophagy in muscular dystrophy to enhance both strength and cardiac function. FASEB J 28:2047-61
Udan-Johns, Maria; Bengoechea, Rocio; Bell, Shaughn et al. (2014) Prion-like nuclear aggregation of TDP-43 during heat shock is regulated by HSP40/70 chaperones. Hum Mol Genet 23:157-70
Ching, James K; Elizabeth, Sarita V; Ju, Jeong-Sun et al. (2013) mTOR dysfunction contributes to vacuolar pathology and weakness in valosin-containing protein associated inclusion body myopathy. Hum Mol Genet 22:1167-79
Benatar, Michael; Wuu, Joanne; Fernandez, Catalina et al. (2013) Motor neuron involvement in multisystem proteinopathy: implications for ALS. Neurology 80:1874-80
Weihl, Conrad C (2013) Monitoring autophagy in the treatment of protein aggregate diseases: steps toward identifying autophagic biomarkers. Neurotherapeutics 10:383-90
Ching, James K; Weihl, Conrad C (2013) Rapamycin-induced autophagy aggravates pathology and weakness in a mouse model of VCP-associated myopathy. Autophagy 9:799-800