Wiskott-Aldrich syndrome (WAS) is an X chromosome-linked recessive disorder characterized by a crinical triad of eczema, thrombocytopenia and immunodeficiency. The gene responsible for this disorder was identified and shown to encode a multi-domain protein, Wiskott-Aldrich syndrome protein (WASP). WASP stimulates actin assembly through its C-terminus, but the physiological roles of the WASP N-terminus remain unknown.The principle investigator, I have identified calcium integrin binding protein (CIB) as a WASP N-terminus binding partner. The preliminary results suggest that WASP and CIB may participate in platelet aggregation and leukocyte migration by modulating integrins' affinities for their ligands. And also, I have isolated a cDNA encoding a novel WASP N-terminus-interacting protein (WIP-2). WJP-2 sequence suggests that WIP-2 is involved in chemotaxis. Based on these critical findings, to understand the roles of the WASP N-terminus in hematopoietic cells, the following specific aims are proposed.I. To elucidate the molecular mechanisms underlying the affinity modulation of integrin allb(33 for its ligand by WASP, CIB and PIP2 in platelets. II. To determine the molecular basis underlying bleeding in XLT patients. III. To determine the roles of WASP and CLB in chemotactic migration of leukocytes. IV. To determine the roles of a novel WASP N-terminus interacting protein (WIP-2) in Ieukocyte migration.Elucidating the roles of the WASP N-terminus in hematopoietic cells will provide important information about critical biological processes such as cell migration, and it should facilitate the development of potential therapeutic agent to treat XLT and WAS

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD042752-01
Application #
6522057
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Hewitt, Tyl
Project Start
2002-06-01
Project End
2007-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
1
Fiscal Year
2002
Total Cost
$267,300
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
009214214
City
La Jolla
State
CA
Country
United States
Zip Code
92037