The goal of this research project is to increase the understanding of the role of erythrocyte alpha-spectrin in both erythroid and non-erythroid murine tissues. Deficiencies of membrane-bound erythrocyte alpha-spectrin result in a severe hemolytic anemia in spherocytic mice and can cause a similar phenotype in humans. Histological examination of two of the spherocytic mutations in mice reveals evidence of thrombi, emboli, and infarctions in the brain and cardiac tissues that may be secondary effects of the anemia or primary effects of tissue-specific alpha-spectrin deficiency. It is known, for example that erythroid alpha-spectrin is present in the brain. Northern blot and in situ hybridization will be used to extend expression studies of the erythroid alpha-spectrin gene in normal erythroid and non-erythroid tissues. Similar analyses will be used to identify changes in erythroid alpha-spectrin gene expression in erythroid and non-erythroid tissues from spherocytic mice. Based upon the results of these analyses, RT-PCR, PCR, and sequencing will be used to identify the mutation in the alpha-spectrin gene associated with one of the spherocytic mutant mouse lines. Finally, bone marrow transplantation will be used to determine if the thrombi, emboli, and infarctions in the brain and heart tissues of spherocytic mice arise due to erythroid alpha-spectrin deficiency in hematopoietic cells. Further histological analyses will also be used to define the developmental age at which these histological anomalies occur. These studies will identify cell types in which a deficiency of erythrocyte alpha-spectrin alters structural integrity and function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK009482-02
Application #
2443885
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Bishop, Terry Rogers
Project Start
1997-07-01
Project End
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609