One age associated muscle disorder is due to mutations in valosin containing protein (VCP) which causes IBMPFD/ALS or inclusion body myopathy (IBM) associated with Paget's disease of the bone (PDB), fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Muscle weakness is the most prevalent phenotypic feature. Although IBMPFD itself is rare, the culmination of each component (IBM, PDB, FTD and ALS) makes its incidence more common in the general population. VCP mutations disrupt autophagosome maturation resulting in dysfunctional autophagy and muscle weakness. In addition, they disrupt mTORC1 signaling. We propose to 1) identify the molecular complex essential for VCP mediation autophagy;2) understand the role for VCP in amino acid stimulated mTORC1 activity. 3) Modulate mTORC1 activity as a therapeutic intervention in IBMPFD/ALS. This proposal will extend the observations and published results from the applicant over the past 5 years.

Public Health Relevance

Pathologic protein inclusions accumulate in many divergent disease states associated with aging like inclusion body myositis and dementia. We hypothesize that an impairment in autophagy and autophagy signaling pathways conferred by mutations in the protein VCP results in inclusion body myopathy associated with Paget's disease of the bone, fronto-temporal dementia and amyotrophic lateral sclerosis (IBMPFD/ALS). Understanding IBMPFD/ALS will lend insight into the treatment of other more common age related disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG031867-06
Application #
8631899
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Velazquez, Jose M
Project Start
2009-01-01
Project End
2018-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
6
Fiscal Year
2014
Total Cost
$311,600
Indirect Cost
$106,600
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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