The research deals with platelet adhesion in arteries, focusing on an adhesion receptor, platelet glycoprotein (GP) lb. The long-term objective is to characterize genes, genetic defects, transcripts and polypeptides that relate to GP lb. Circulating platelets function as monitors of the endothelial lining of blood vessels, sticking to areas with exposed subendothelium. At sites of vascular injury, platelet adhesion or """"""""sticking"""""""" initiates normal platelet plug formation that stops blood loss. At sites of vascular disease, however, platelet adhesion sets off abnormal thrombosis that leads to heart attacks and strokes. In the arterial circulation, platelet surface glycoprotein lb serves as the contact point for adhesion by binding von Willebrand factor and using it as a link to the vascular surface. Two other surface glycoproteins, GP V and GP IX, are related to GP lb through common structural elements (leucine-rich glycoprotein sequences) and a common congenital deficiency state (Bernard-Soulier syndrome). GP lb and GP IX associate directly in the GP lb-IX complex. Stemming from four genes (lb alpha/lb beta/V/IX) dispersed on separate chromosomes, the three proteins, GP lb/V/IX appear to work in concert to produce a functional surface GP lb receptor. This proposal asks, """"""""What relationships coordinate the lb/V/IX system?"""""""" """"""""Do the genes share common structures, particularly promoters?"""""""" """"""""Does a common mechanism regulate gene expression?"""""""" """"""""Can one gene defect cause a congenital deficiency of the three surface GP's?"""""""" """"""""Can transfected cDNAs produce a mature surface GP lb receptor?"""""""" Specific Aims and Experimental Approach 1. Clone and characterize the cDNA encoding human platelet glycoprotein V. 2. Clone and characterize genomic DNA encoding glycoproteins Ibbeta, V, and IX. 3. Characterize the genetic defect in two cases of Bernard Soulier syndrome. 4. Characterize the transcriptional response of the lbalpha, lbbeta, V, IX genes. 5. Assess the structure and function of lbalpha using transfected cDNAs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL039947-04
Application #
3356961
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1988-04-01
Project End
1996-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Yagi, M; Roth, G J (2006) Megakaryocyte polyploidization is associated with decreased expression of polo-like kinase (PLK). J Thromb Haemost 4:2028-34
Bastian, L S; Kwiatkowski, B A; Breininger, J et al. (1999) Regulation of the megakaryocytic glycoprotein IX promoter by the oncogenic Ets transcription factor Fli-1. Blood 93:2637-44
Yagi, M; Ritchie, K A; Sitnicka, E et al. (1999) Sustained ex vivo expansion of hematopoietic stem cells mediated by thrombopoietin. Proc Natl Acad Sci U S A 96:8126-31
Yagi, M; Zieger, B; Roth, G J et al. (1998) Structure and expression of the human septin gene HCDCREL-1. Gene 212:229-36
Calverley, D C; Kavanagh, T J; Roth, G J (1998) Human signaling protein 14-3-3zeta interacts with platelet glycoprotein Ib subunits Ibalpha and Ibbeta. Blood 91:1295-303
Li, C; Pasquale, D N; Roth, G J (1996) Bernard-Soulier syndrome with severe bleeding: absent platelet glycoprotein Ib alpha due to a homozygous one-base deletion. Thromb Haemost 76:670-4
Bastian, L S; Yagi, M; Chan, C et al. (1996) Analysis of the megakaryocyte glycoprotein IX promoter identifies positive and negative regulatory domains and functional GATA and Ets sites. J Biol Chem 271:18554-60
Roth, G J (1996) Molecular defects in the Bernard-Soulier syndrome: assessment of receptor genes, transcripts and proteins. C R Acad Sci III 319:819-26
Roth, G J; Yagi, M; Bastian, L S (1996) The platelet glycoprotein Ib-V-IX system: regulation of gene expression. Stem Cells 14 Suppl 1:188-93
Yagi, M; Edelhoff, S; Disteche, C M et al. (1995) Human platelet glycoproteins V and IX: mapping of two leucine-rich glycoprotein genes to chromosome 3 and analysis of structures. Biochemistry 34:16132-7

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