DESCRIPTION (provided by applicant): Our laboratory was the first to identify VCP mutations as a cause of hereditary inclusion body myopathy, Paget's disease of bone, frontotemporal dementia and amyotrophic lateral sclerosis, and has made progress in identifying the underlying molecular pathogenesis of these diseases. Studies of patients' myoblasts and the heterozygous R155H mouse have placed VCP at the intersection of the ubiquitin-proteasome signaling and autophagy pathways, both mechanisms being considered responsible for the intracellular protein degradation and abnormal pathology seen in muscle and brain. We have developed the first knock-in VCP mouse model carrying the common R155H mutation, which has many clinical features typical of the human disease (1). Unlike disease progression in the R155H heterozygous (VCPR155H/+) mouse model, homozygotes (VCPR155H/R155H) have a more severe muscle, brain and spinal cord pathology, with most surviving no more than 21 days. Homozygotes demonstrate an abnormal autophagic pathway and mitochondrial proliferation, as evidenced by structural and functional studies. Recent preliminary studies have shown that feeding pregnant heterozygous dams a diet with a 3% increase in fat results in a dramatic improvement in the survival of their homozygous offspring. These offspring live longer than 21 days and are successfully weaned, demonstrating that an increased fat diet ameliorates the lethal phenotype. In this application, we propose to investigate the optimum percentage of fat content on further rescuing the lethal phenotype. We will also study the important altered mitochondrial, autophagy and ubiquitin-proteasome molecular pathways in the homozygous VCP knock-in mice treated with normal versus high-fat diets. Studying this observation affords the opportunity to develop a promising therapeutic strategy for patients with VCP and related diseases. PUBLIC HEALTH RELEVANCE: The knock-in homozygous VCP R155H knock-in mouse demonstrates more severe disease compared to the heterozygous R155H VCP mouse model and dies by 21 days. The mice have many of the pathological features typical of hereditary inclusion body myopathy, Paget disease of bone, frontotemporal dementia (IBMPFD) and ALS associated with mutations in the VCP gene. We have recently identified that we can rescue the lethal phenotype by feeding pregnant dams and pups a higher fat diet. This proposal offers the opportunity of utilizing the knock-in homozygous mice for the necessary preclinical studies before evaluating this promising treatment in patients with VCP disease.

The knock-in homozygous VCP R155H knock-in mouse demonstrates more severe disease compared to the heterozygous R155H VCP mouse model and dies by 21 days. The mice have many of the pathological features typical of hereditary inclusion body myopathy, Paget disease of bone, frontotemporal dementia (IBMPFD) and ALS associated with mutations in the VCP gene. We have recently identified that we can rescue the lethal phenotype by feeding pregnant dams and pups a higher fat diet. This proposal offers the opportunity of utilizing the knock-in homozygous mice for the necessary preclinical studies before evaluating this promising treatment in patients with VCP disease.