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| Ashrafi, Kaveh |
| Barber, Diane L |
| Bernstein, Harold S. |
| Black, Brian L |
| Blanc, Paul D |
| Boushey, Homer A |
| Broaddus, V Courtney |
| Brown, James K |
| Caughey, George H |
| Chapman, Harold A |
| Charo, Israel F |
| Chatterjee, Kanu |
| Chuang, Pao-Tien |
| Clyman, Ronald I |
| Conklin, Bruce R |
| Coughlin, Shaun R |
| Derynck, Rik M |
| Dobbs, Leland G |
| Eisner, Mark D |
| Engel, Joanne N |
| Erle, David J |
| Fahy, John Vincent |
| Farese, Robert V |
| Fielding, Christopher J |
| Fielding, Phoebe |
| Fineman, Jeffrey R |
| Glantz, Stanton A |
| Grossman, William |
| Hawgood, Samuel |
| Ingraham, Holly A |
| Jan, Lily Y |
| Kan, Yuet W |
| Kane, John P |
| Kornberg, Thomas B |
| Kurtz, Theodore W |
| Kwok, Pui-Yan |
| Lazarus, Stephen C |
| Malloy, Mary J. |
| Martin, Gail R |
| Matthay, Michael A |
| Mcdonald, Donald M |
| Mikawa, Takashi |
| Minor, Daniel L |
| Mostov, Keith E |
| Nadel, Jay A |
| Ordahl, Charles P |
| Pitas, Robert E |
| Reiter, Jeremy F. |
| Rosen, Steven D |
| Shaw, Robin M. |
| Sheppard, Dean |
| Simpson, Paul C |
| Stainier, Didier Y. R. |
| Wang, Rong |
| Weiner, Orion D |
| Weisgraber, Karl H |
| Weiss, Arthur |
| Weiss, Ethan J |
| Werb, Zena |
| Wiener-Kronish, Jeanine |
| Young, William L |
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CVRI Scientists
Karl H. Weisgraber, Ph.D.
Senior Investigator, Gladstone Institute of Cardiovascular Disease and Gladstone Institute of Neurological Disease
Research Interests:
Structure-function of apolipoprotein E
Summary:
The current focus of our research is on the structure and function relationships of plasma apolipoprotein (apo) E in both lipoprotein metabolism and Alzheimer's disease. ApoE is a 299 residue, single chain protein that contains two structural domains, an amino- and carboxyl-terminal domain that also defines functional domains. The amino-terminal domain (residues 1Ð191) contains the LDL receptor binding region of apoE and the carboxyl-terminal domain contains the major lipid binding elements. Previous studies have established that the three common isoforms of apoE, apoE2, apoE3, and apoE4, which differ by cysteine and arginine contents at two positions in the molecule, have very different metabolic properties with a dramatic impact on two diseases. For example, apoE3 (Cys-112, Arg-158) binds normally to the low density lipoprotein (LDL) receptors and is associated with normal metabolism, whereas apoE2 (Cys-112, Cys-258) binds defectively and is associated with the genetic lipoprotein disorder, type III hyperlipoproteinemia. The apoE4 allele is a major risk factor for Alzheimer's disease and other neurodegenerative diseases; apoE4 is also associated with elevated cholesterol levels and an increased risk for heart disease, although it binds normally to LDL receptors.
In our research, physical-chemical techniques, including x-ray crystallography, are combined with site-directed mutagenesis to probe structure and function questions. We have identified two unique properties of apoE4 compared to apoE3 and apoE2: domain interaction and low stability to unfolding. It is our working hypothesis that either or both of these properties account for the association of apoE4 with disease. To distinguish between the relative contribution of domain interaction and stability to the known effects of apoE4, we have taken advantage of the fact that mouse apoE does not display either property. By identifying the key residues in apoE4 that contribute to domain interaction and stability, we have introduced each property selectively into a mouse model by gene targeting. Our overall goal is to determine how structural changes in apoE influence its known metabolic properties and contribute to the isoform-specific effects in lipoprotein metabolism, heart disease, and Alzheimer's disease.
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