Mutations in valosin-containing prote in (VCP) cause a rare complex disorder called inclusion body myopathy associated with Paget disease ofthe bone and frontotemporal dementia (IBMPFD). The exact underlying molecular and cellular pathogenic a nd degenerative mechanisms mediated by mutant VCP remain unl In Aim 1, we will investigate the underlying molecular mechanisms by which mutant VCP impairs autophagy in cell culture models, and how these impairments impact on protein accumulations and innate inflammatory responses.
In Aim 2, we will generate a novel induci ble transgenic mouse harboring a clinical mutation in the VCP gene as a model for IBMPFD. This transgenic model will provide insight into the m olecular mechanisms of the disease, and will serve as a valuable tool for preclinical therapeutic interventions. The inducible VCP mouse model is significant for the field and offers several distinct and significant advantages: (1) it is only one of a few models for IBMPFD;(2) mutant VCP expression can not only be limited to specific tissue(s) based on the research interest, but also be turn on and off during the lifespan of the mouse;and (3) by limiting mutant VCP expression, we are able to avoid confounding complications. We believe that our proposed pr eject will advance our understandin gs in IBMPFD and related VCP diseases and help developing effective therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Transition Award (R00)
Project #
5R00AR054695-05
Application #
8660646
Study Section
Special Emphasis Panel (NSS)
Program Officer
Boyce, Amanda T
Project Start
2012-04-09
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2014
Total Cost
$233,482
Indirect Cost
$16,569
Name
University of California Merced
Department
None
Type
Schools of Earth Sciences/Natur
DUNS #
113645084
City
Merced
State
CA
Country
United States
Zip Code
95343