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 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.
|Rodriguez-Ortiz, Carlos J; Flores, Julio C; Valenzuela, Joanna A et al. (2016) The Myoblast C2C12 Transfected with Mutant Valosin-Containing Protein Exhibits Delayed Stress Granule Resolution on Oxidative Stress. Am J Pathol 186:1623-34|
|Rodriguez-Ortiz, Carlos J; Hoshino, Hitomi; Cheng, David et al. (2013) Neuronal-specific overexpression of a mutant valosin-containing protein associated with IBMPFD promotes aberrant ubiquitin and TDP-43 accumulation and cognitive dysfunction in transgenic mice. Am J Pathol 183:504-15|
|Nalbandian, Angèle; Llewellyn, Katrina J; Kitazawa, Masashi et al. (2012) The homozygote VCP(R¹??H/R¹??H) mouse model exhibits accelerated human VCP-associated disease pathology. PLoS One 7:e46308|