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.
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.
|Papadopoulos, Chrisovalantis; Kirchner, Philipp; Bug, Monika et al. (2017) VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy. EMBO J 36:135-150|
|Bamaga, Ahmed K; Weihl, Conrad C (2017) Establishing prevalence in rare neuromuscular diseases: A lesson from congenital myopathies. Neurol Genet 3:e146|
|Güttsches, Anne-Katrin; Brady, Stefen; Krause, Kathryn et al. (2017) Proteomics of rimmed vacuoles define new risk allele in inclusion body myositis. Ann Neurol 81:227-239|
|Lee, YouJin; Chou, Tsui-Fen; Pittman, Sara K et al. (2017) Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination. Cell Rep 19:188-202|
|Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222|
|Bhattacharya, Martha R C; Geisler, Stefanie; Pittman, Sara K et al. (2016) TMEM184b Promotes Axon Degeneration and Neuromuscular Junction Maintenance. J Neurosci 36:4681-9|
|Zhang, Xiaoyi; Gui, Lin; Zhang, Xiaoyan et al. (2015) Altered cofactor regulation with disease-associated p97/VCP mutations. Proc Natl Acad Sci U S A 112:E1705-14|
|Crisp, Matthew J; Mawuenyega, Kwasi G; Patterson, Bruce W et al. (2015) In vivo kinetic approach reveals slow SOD1 turnover in the CNS. J Clin Invest 125:2772-80|
|Jerath, Nivedita U; Crockett, Cameron D; Moore, Steven A et al. (2015) Rare Manifestation of a c.290 C>T, p.Gly97Glu VCP Mutation. Case Rep Genet 2015:239167|
|Weihl, Conrad C; Baloh, Robert H; Lee, Youjin et al. (2015) Targeted sequencing and identification of genetic variants in sporadic inclusion body myositis. Neuromuscul Disord 25:289-96|
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