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2007 Grant - Xu
Characterizing a Novel Gene That Inhibits GSK3 Activity and Beta-Amyloid Generation
Huaxi Xu, Ph.D.
Burnham Institute for Medical Research
La Jolla, California
Candidate for 2007 Zenith Fellows Award
Many scientists consider the protein fragment beta amyloid to be a key suspect in Alzheimer's disease pathology. Beta-amyloid is produced from amyloid precursor protein (APP) by the action of two separate enzymes: beta-secretase, which makes the first cut, and gamma-secretase, which makes the second. Both enzymes have attracted strong interest as potential therapeutic targets because blocking the activity of either one would stop beta-amyloid production.
In preliminary studies with mice and laboratory cells, Huaxi Xu, Ph.D., and colleagues have identified a gene that can inhibit gamma-secretase from producing beta-amyloid. Known as FG01, this gene has proven especially useful because it does not affect the helpful actions of gamma-secretase toward other proteins. Dr. Xu's group has also found that FG01 encodes a protein that, when overexpressed in cells, can reduce the harmful activities an enzyme called glycogen synthase kinase-3 (GSK3). GSK3 plays key roles in such disease processes as cancer and diabetes.
For this proposed grant, Dr. Xu's team will more closely analyze FG01's biological features and its mechanisms of action. The researchers will then use mice genetically engineered to overexpress FG01 to further test the gene's ability to reduce beta-amyloid and GSK3 activities. Such work could lead to novel, safe therapies for Alzheimer's and other diseases.