The long term objective of this proposal is to elucidate the mechanism of outside-in signal transduction mediated by the platelet fibrinogen receptor, the integrin alphaIIb/beta3. Elucidation of the mechanism of outside-signal transduction in human platelets is important basic research. This research is important not only because of the central role of platelets in cardiovascular disease but also because insight into the mechanism of outside-in signal transduction is of central importance to cell biology in general. Gaining insight into the molecular details of outside-in signal transduction in platelets may provide a rationale for the design of a pharmaceutical agent able to control at least some of the platelet behavior which contributes to development and progression of cardiovascular disease. The long term objective of this proposal will be accomplished by characterizing the effects of a unique receptor activating peptide on platelet function. This receptor activating peptide appears to cause platelet aggregation by binding to alphaIIb and thereby eliciting a conformation change in the fibrinogen receptor which initiates a platelet activation signal transduction cascade that culminates in """"""""irreversible"""""""" platelet aggregation. The experiments described in this proposal are designed to reveal how binding of the receptor activating peptide to the receptor elicits outside-in signal transduction. Hopefully, these experiments will reveal the type of intra-receptor subunit or inter-receptor interactions which initiate the outside-in signal transduction response in platelets and identify the major components of the signal transduction pathway used to propagate this outside-in signaling.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL063216-01A2
Application #
6334125
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Ganguly, Pankaj
Project Start
2001-05-01
Project End
2004-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
1
Fiscal Year
2001
Total Cost
$241,729
Indirect Cost
Name
University of Memphis
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
City
Memphis
State
TN
Country
United States
Zip Code
38152
Niu, Haixia; Chen, Xue; Gruppo, Ralph A et al. (2012) Integrin ?IIb-mediated PI3K/Akt activation in platelets. PLoS One 7:e47356
Niu, Haixia; Xu, Zhenlu; Li, Ding et al. (2012) Peptide LSARLAF induces integrin ?3 dependent outside-in signaling in platelets. Thromb Res 130:203-9
Liu, J; Joglekar, M; Ware, J et al. (2008) Evaluation of the physiological significance of botrocetin/ von Willebrand factor in vitro signaling. J Thromb Haemost 6:1915-22
Liu, J; Jackson, C W; Gartner, T K (2008) The Src requirement for washed platelet aggregation and dense granule secretion in response to stimulation by a low level gamma-thrombin. J Thromb Haemost 6:1035-7
Liu, J; Ware, J; Jackson, C W et al. (2007) FcRgamma-chain-dependent alphaIIbeta3 elicited outside-in signaling. J Thromb Haemost 5:426-8
Liu, J; Ware, J; Jackson, C W et al. (2007) FcRgamma-chain signals in the absence of glycoprotein VI. J Thromb Haemost 5:201-3
Liu, Junling; Jackson, Carl W; Gruppo, Ralph A et al. (2005) The beta3 subunit of the integrin alphaIIbbeta3 regulates alphaIIb-mediated outside-in signaling. Blood 105:4345-52
Liu, Junling; Pestina, Tamara I; Berndt, Michael C et al. (2005) Botrocetin/VWF-induced signaling through GPIb-IX-V produces TxA2 in an alphaIIbbeta3- and aggregation-independent manner. Blood 106:2750-6
Liu, J; Pestina, T I; Berndt, M C et al. (2004) The roles of ADP and TXA in botrocetin/VWF-induced aggregation of washed platelets. J Thromb Haemost 2:2213-22
Cho, M J; Liu, J; Pestina, T I et al. (2003) AlphaIIbbeta3-mediated outside-in signaling induced by the agonist peptide LSARLAF utilizes ADP and thromboxane A2 receptors to cause alpha-granule secretion by platelets. J Thromb Haemost 1:363-73

Showing the most recent 10 out of 13 publications