The candidate has two years post-doctoral and three years research-scientist experience, and is currently being proposed for an Assistant Professor appointment at School of Medicine of Yale University. This application for a mentored K01 award is submitted with the goal of providing the candidate with the further training experience to function as an independent investigator working in the field of liver cell biology. The project's long-term objectives are to understand the mechanisms that underlie the degradation of hepatic transporters in a number of hereditary diseases including cholestasis. This is a prerequisite for developing novel stratagies to overcome the bile secretion defect in hereditary cholestasis and such stratagies may also apply to other genetic diseases such as cystic fibrosis. We and others have demonstrated that in hereditary cholestasis and Dubin-Johnson syndrome genetic mutations lead to the intracellular retention and subsequent degradation of the bile salt export pump (BSEP) and the multidrug resistance protein 2 (MRP2) by proteasomes. This leads to the hypothesis that endoplasmic reticulum-associated protein degradation (ERAD) and ubiquitination enzymes are responsible for the degradation of the BSEP and MRP2 in these disorders. The preliminary data demonstrates that a novel ubiquitin ligase targets one mutant of BSEP to degradation. The candidate proposes to I) Characterize the different cellular pathways in the degradation of the BSEP mutants in hereditary cholestasis. II) Determine the ubiqutin ligase(s) that target BSEP mutants to degradation. III) Examine the ERAD-specific ubiquitin conjugating enzymes in the degradation of the BSEP mutants. IV) Establish whether the primary ubiquitin ligase responsible for the ERAD of BSEP also targets the mutants of other ABC transporters such as MRP2 and CFTR protein in Dubin-Johnson syndrome and cystic firbosis. The Section of Digestive Diseases and Department of Molecular Biophysics and Biochemistry at Yale University are ideal for carrying out such studies because of the quality of their faculty, their experience as mentors and the core facility at the Yale Liver Center. The School of Medicine has pledged protected time for the candidate during this further training period prior to functioning as an independent investigator.
|Wang, Lin; Dong, Huiping; Soroka, Carol J et al. (2008) Degradation of the bile salt export pump at endoplasmic reticulum in progressive familial intrahepatic cholestasis type II. Hepatology 48:1558-69|
|Arteaga, Maria Francisca; Wang, Lin; Ravid, Tommer et al. (2006) An amphipathic helix targets serum and glucocorticoid-induced kinase 1 to the endoplasmic reticulum-associated ubiquitin-conjugation machinery. Proc Natl Acad Sci U S A 103:11178-83|