Request for Funding

Medical Student Research Fellowship for Summer 2001

Mentor: Helen H. Hobbs

Department: Molecular Genetics and Internal Medicine

Room number: L5.134

Mail Code: 9046

Phone number: 214-648-6724

E-mail: Helen.hobbs@email.swmed.edu

Project title: Specificity and Physiological Significance of ARH Interaction with LDLR

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: We have identified a gene that is defective in an autosomal recessive form of hypercholesterolemia that is characterized by a tissue-specific defect in LDL receptor function. LDL receptor activity is normal or only slightly impaired in fibroblasts but is absent in the liver of subjects with mutations in the ARH gene. ARH encodes a putative adaptor protein that contains a phosphotyrosine binding domain at is N-terminus and has conserved sequences at its C-terminus. PTB domains have been shown to interact with a sequence motif found in the cytoplasmic domain of the LDL receptor, and we have in vitro evidence suggesting that this occurs in vivo. The goal of this project will be optimize and further characterize this interaction using mammalian two-hybrids and the fluorescence resonance energy transfer technique.

Previous Research Activities or Publications with Medical Students:

1999, Shaine Muller: Collected and characterized large family with familial combined hyperlipidemia and initiated genome scan to map the gene responsible for this autosomal dyslipidemia

1999, Harshal Broker: Characterized the genes encoding lactate transporters in muscle in preparation for screening these genes for sequence variations in navy recruits that develop rhabdomyalasis during training

1997, Ting-chi Lu: Examined the role of a newly discovered HDL receptor in the clearance of lipopolysaccaride (endotoxin).

1996, Jeremy Cuthbertson: Performed segregation analysis of the apo(a) gene in African-American families

1995, Moeen Aberdin: Assisted in the purification of a peptide from the urine that is generated from apo(a)

1995, Lori Probst- Characterization of gene encoding sterol regulatory element binding protein 2

I have had at least one medical student in my lab every summer between 1989-1995

Publications:

Leitersdorf, E., E.J. Tobin, J. Davignon, and H.H. Hobbs. 1990. "Common Low-density Lipoprotein Receptor Mutations in the French Canadian Population," J. Clin. Invest. 85:1014-1023.

Mooser, V., M.C. Seabra, M. Abedin, K.T. Landschulz, S. Marcovina, and H.H. Hobbs. 1996. Apolipoprotein(a) Kringle 4-Containing Fragments in Human Urine. J. Clin. Invest. 97:858-864.

Miserez, A.R., G. Cao, L.C. Probst, and H.H. Hobbs. 1997. Structure of the Human Gene Encoding Sterol Regulatory Element Binding Protein 2 (SREBF2). Genomics. 40:31-40.

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