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2011 Grants - Sisodia
Functional Analysis of Nicastrin
Sangram S. Sisodia, Ph.D.
University of Chicago
2011 Investigator-Initiated Research Grant
One molecule at the focus of research into the causes of Alzheimer's disease is beta-amyloid, a protein fragment produced from its parent protein through the action of enzyme complexes. One key enzyme complex involved in the production of beta-amyloid is gamma-secretase, of which the protein nicastrin is a crucial component. Nicastrin recognizes the parent molecule of beta-amyloid as well as numerous other proteins that are processed by the gamma-secretase complex.
One potential strategy for slowing the progression of Alzheimer's disease is to inhibit the production of beta-amyloid by inhibiting gamma-secretase. For this strategy to be successful, however, processing of other proteins by gamma-secretase must not be inhibited.
Sangram S. Sisodia, Ph.D. and colleagues have proposed a series of studies to investigate the structure of nicastrin and how it recognizes the correct proteins to be processed by gamma-secretase. The researchers use a technology known as synthetic antigen binding (SAB) to develop drug-like molecules that bind to specific regions of nicastrin. They are then able to use these molecules to probe how different regions of nicastrin function.
Dr. Sisodia and colleagues plan to examine how different SAB molecules affect the ability of nicastrin to recognize different proteins. They also plan to use SAB molecules to aid in the production of crystals of nicastrin, which can then be studied by x-ray crystallography to determine the protein's structure. The ultimate goal of this research is to develop drug candidates that prevent gamma-secretase from producing beta-amyloid but that do not interfere with its other functions.