Sickle cell disease arises from a genetic mutation in the adult beta-globin protein which results in the substitution of a valine for glutamic acid in position 6 of the molecule. It is a disease of chronic anemia that exhibits a complex pathophysiology. Although much is known about the disease, there is no cure or effective treatment currently available. A major impediment towards a detailed understanding of this disease and to the development of effective treatments is the lack of a suitable animal model. To provide systems allowing examination of chronic sickle cell disease events, a major focus of research effort has been the creation of transgenic mouse models. The introduction of human beta-s gene have, however, not created successful models due in part to expression rates of the transgene and the incompatibility of human and mouse globin proteins. Therefore, the investigators believe that a better model of sickle cell disease can be created by manipulation of the endogenous mouse betaMAJ gene. The investigators will test the hypothesis using a combined in vitro and in vivo approach. First, the investigators will express mouse globin in bacteria (Zimmer, 1996) then assay the expressed proteins, both normal and mutant, for oxygen carrying capacity and polymer formation. The investigators will utilize state of the art molecular modeling to guide the creation of mutant mouse beta globins that enhances polymer function. The investigators will then translate their in vitro knowledge to a mouse model by placing the appropriate mutations into the betaMAJ globin gene within mouse genome. This will use the technologies of targeted oblation (Zimmer, 1995) and replacement with the mutant betaMAJ gene sequences. The studies will create an animal model that more closely resembles the human disease. This will be key in understanding of the complex pathophysiology of sickle cell disease as well as a powerful tool to examine potential therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Comprehensive Center (P60)
Project #
5P60HL038639-15
Application #
6589044
Study Section
Project Start
2002-04-15
Project End
2003-03-31
Budget Start
Budget End
Support Year
15
Fiscal Year
2002
Total Cost
Indirect Cost
Name
University of South Alabama
Department
Type
DUNS #
City
Mobile
State
AL
Country
United States
Zip Code
36688
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