Platelet GPVI and integrin alpha 2/beta 1 cooperate closely to mediate effective platelet adhesion to collagens and subsequent platelet procoagulant activity. In preliminary findings, we have observed that the levels of platelet GPVI vary in parallel with those of alpha 2/beta 1. Differences in the density of alpha 2/beta 1 or GPVI in themselves may not compromise platelet function in otherwise healthy individuals, but they can influence clinical outcomes in individuals who are at increased risk for thrombosis or bleeding. In order to develop a comprehensive understanding of platelet adhesion to collagens, our goal is to study the molecular biology of both integrin alpha 2/beta 1 and platelet GPVI. The focus of this grant is the latter receptor, platelet GPVI. To accomplish our goal, we have developed new resources: First, we have isolated a BAC plasmid containing the human GPVI gene, and we have assembled the complete human gene sequence. Second, we have cloned and sequenced murine platelet GPVI cDNA, and the knowledge of this sequence was employed to isolate BAC plasmids containing the complete murine GPVI gene. With these resources, then, the Specific Aims of this application are: 1) To analyze the platelet content of GPVI vis-a-vis the density of integrin alpha 2/beta 1 among normal individuals and to assess the effect of receptor variation on platelet procoagulant activity and platelet adhesion to collagens; 2) To characterize the binding sites on GPVI for collagen and convulxin (CVX); 3) To characterize the human GPVI gene and define the molecular basis for variation in platelet GPVI expression; and 4) To develop a mouse model for GPVI deficiency using transgenic technology. The successful completion of the proposed studies will lead to a substantial increase in our understanding of the genetics and physiology of the platelet collagen receptor, GPVI.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL046979-12
Application #
6530654
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Ganguly, Pankaj
Project Start
1992-04-01
Project End
2005-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
12
Fiscal Year
2002
Total Cost
$370,400
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Kunicki, Thomas J; Williams, Shirley A; Nugent, Diane J et al. (2012) Mean platelet volume and integrin alleles correlate with levels of integrins ?(IIb)?(3) and ?(2)?(1) in acute coronary syndrome patients and normal subjects. Arterioscler Thromb Vasc Biol 32:147-52
Kunicki, T J; Baronciani, L; Canciani, M T et al. (2006) An association of candidate gene haplotypes and bleeding severity in von Willebrand disease type 2A, 2B, and 2M pedigrees. J Thromb Haemost 4:137-47
Kanaji, Sachiko; Kanaji, Taisuke; Jacquelin, Beatrice et al. (2005) Thrombopoietin initiates demethylation-based transcription of GP6 during megakaryocyte differentiation. Blood 105:3888-92
Kunicki, Thomas J; Cheli, Yann; Moroi, Masaaki et al. (2005) The influence of N-linked glycosylation on the function of platelet glycoprotein VI. Blood 106:2744-9
Kunicki, Thomas J; Federici, Augusto B; Salomon, Daniel R et al. (2004) An association of candidate gene haplotypes and bleeding severity in von Willebrand disease (VWD) type 1 pedigrees. Blood 104:2359-67
Vasudevan, Sona; Celikel, Reha; Ruggeri, Zaverio M et al. (2004) A single amino acid change in the binding pocket alters specificity of an anti-integrin antibody AP7.4 as revealed by its crystal structure. Blood Cells Mol Dis 32:176-81
Kanaji, Sachiko; Kanaji, Taisuke; Furihata, Kenichi et al. (2003) Convulxin binds to native, human glycoprotein Ib alpha. J Biol Chem 278:39452-60
Kunicki, Thomas J (2002) The influence of platelet collagen receptor polymorphisms in hemostasis and thrombotic disease. Arterioscler Thromb Vasc Biol 22:14-20
Jacquelin, B; Tarantino, M D; Kritzik, M et al. (2001) Allele-dependent transcriptional regulation of the human integrin alpha2 gene. Blood 97:1721-6
Santoso, S; Kunicki, T (2001) Platelet receptor polymorphisms and thrombotic risk. Ital Heart J 2:811-5

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