Medical Student Research Fellowship for Summer 2007

Mentor: Jay D. Horton
Department: Internal Medicine and Molecular Genetics
Room number: L5.230
Mail Code: 9046
Phone number: 648-9677
E-mail: jay.horton@utsouthwestern.edu
Project title:

Human subjects IRB approved project number (where applicable):

Animal subjects IRB approved project number (where applicable):

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects). Basic Research

Brief Description of Project:

Post-transcriptional Regulation of the LDL receptor-A focus of this study is the functional characterization Pcsk9, a gene that encodes proprotein convertase subtilisin/kexin type 9a. PCSK9 belongs to the proteinase K subfamily of subtilases and is synthesized as a soluble zymogen that undergoes autocatalytic intermolecular processing in the ER, which results in the cleavage of its prosegment that remains associated with the secreted enzyme. We have carried out a series of in vitro and in vivo studies that demonstrated PCSK9 overexpression decreases LDL receptor (LDLR) protein levels, thereby increasing plasma LDL levels. Conversely, the deletion of PCSK9 increases LDLR protein and reduces plasma LDL cholesterol. Additional studies are currently ongoing to define the mechanism by which PCSK9 post-transcriptionally regulates LDL receptor protein levels in liver. The specific projects that could be available and completed during the summer months include 1) mapping the region of PCSK9 that specifically binds to the LDLR or 2) Make and purify mutant PCSK9 proteins and assess their ability to bind and degrade the LDLR protein.

Previous Research Activities or Publications with Medical Students:

T. A. Lagace, D. E. Curtis, R. Garuti, M. C. McNutt, S. W. Park, H. B. Prather, N. N. Anderson, Y. K. Ho, R. E. Hammer, and J. D. Horton. 2006. Secreted PCSK9 decreases LDL receptors in hepatocytes and livers of parabiotic mice. J. Clin. Invest. 116:2995-3005.

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