Deficient function of Bruton's tyrosine kinase (Btk) results in the human B cell immunodeficiency, X-linked agammaglobulinemia (XLA), which is characterized by failure of developing and immature B cells to respond to signals controlling both the pre-B to immature B cells, and the naïve to activated B cell transitions. B cell activation, transcription, and proliferation are dependent upon the level and duration of the increased intracellular calcium ([Ca2+]i)which occurs in response to B cell antigen receptor (BCR) crosslinking. Our preliminary data demonstrate that Btk uniquely regulates sustained increases in [Ca2+]i and functions at a critical crossroads in the events regulating both positive and negative calcium signaling. Together, the failure of Btk-deficient cells to proliferate, and the Btk-dependent enhancement of sustained calcium signaling following BCR crosslinking suggest that Btk provides a calcium dependent signal(s) critical for B lineage survival and/or growth. In the proposed studies we will further define the mechanisms by which Btk family kinases maintain sustained calcium influx; identify the Btk-dependent downstream transcriptional events regulating B lineage development; and evaluate the developmental consequences of dysregulated Btk-dependent calcium signaling. A better understanding of these events will have important implications for both our understanding of normal immune cell development and ultimately for the management of XLA and other primary immunodeficiencies.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD037091-01
Application #
2737014
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Hewitt, Tyl
Project Start
1999-03-01
Project End
2004-02-29
Budget Start
1999-03-01
Budget End
2000-02-29
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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