Investigations in our laboratory will continue to be directed toward development of knowledge of blood platelet function in normal hemostasis, their role in the pathogenesis of inherited and acquired bleeding disorders, and their contribution to protection and injury of blood vessels, thrombosis and arteriosclerosis. Analytical, scanning and transmission electron microscopy, freeze-fracture, cytochemistry, immunofluorescence and immunoelectron microscopy, together with cyclic nucleotide, adenine nucleotide and eicosanoid biochemistry and advanced physiological techniques, including measurements of calcium levels and flux with Quin 2 and Fura 2, micropipette elastimetry, the Baumgartner technique and lumiaggregometry will be used to develop new information on these problems and related areas. Emphasis has been placed on six specific aims.
Specific aim 1 will elucidate the role of membranes and membrane systems in platelet stimulus activation coupling with particular attention to calcium regulation. Approaches to the cytoskeleton in specific aim 2 will reveal its role in platelet resistance to deformation, the asociations between circumferential microtubule coils resulting in support of discoid shape and the interactions between actin microfilaments, microtubules and the cell membrane.
Specific aim 3 will resolve current controversies regarding mechanisms of platelet secretion. A new model of platelet stimulus-activation-contraction-secretion coupling has resulted from our preliminary studies and will serve as the basis for new investigations on the subject in specific aim 4. The relationship between platelet deformability and platelet-vessel wall interaction will be explored in specific aim 5 and may serve as a new basis for selecting anti-platelet drugs and following patients with hyperlipidemia. The 6th specific aim will continue studies on established platelet disorders and explore three new conditions in which abnormal structure may be related to defects in regulation of calcium flux. Accomplishment of these aims in the next five years will bring us very close to achieving the overall goals guiding this project.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL011880-26
Application #
2214667
Study Section
Special Emphasis Panel (NSS)
Project Start
1977-04-01
Project End
1997-01-31
Budget Start
1994-02-01
Budget End
1995-01-31
Support Year
26
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Rao, G H; Escolar, G; White, J R et al. (2001) Differential response of human and bovine platelets to bovine von Willebrand factor and vascular subendothelium. Platelets 12:150-5
Rao, G H; Peller, J D; White, J G (1997) Influence of ionized calcium on thrombin-induced down regulation of GPIb/IX receptors on human platelets. Thromb Res 85:23-31
White, J G; Rao, G H (1996) Aggregated-disaggregated, refractory platelets retain sensitivity to ristocetin. Thromb Res 84:253-66
Rao, G H; Parthasarathy, S (1996) Antioxidants, atherosclerosis and thrombosis. Prostaglandins Leukot Essent Fatty Acids 54:155-66
White, J G; Krumwiede, M D; Cocking-Johnson, D et al. (1996) Prelabeled glycoprotein Ib/IX receptors are not cleared from exposed surfaces of thrombin-activated platelets. Am J Pathol 149:629-38
Rao, G H; Peller, J D; Knopman, D S et al. (1996) Physiology and function of platelets from patients with Alzheimer's disease. Indian J Physiol Pharmacol 40:5-14
White, J G; Escolar, G (1996) Fate of the GPIb/IX receptor complex following activation of human platelets. Blood Coagul Fibrinolysis 7:262-5
White, J G; Krumwiede, M D; Cocking-Johnson, D J et al. (1996) Uptake of vWF-anti-vWF complexes by platelets in suspension. Arterioscler Thromb Vasc Biol 16:868-77
Escolar, G; Diaz-Ricart, M; White, J G (1995) Talin does not associate exclusively with alpha 2b beta 3 integrin in activated human platelets. J Lab Clin Med 125:597-607
White, J G; Krumwiede, M D; Cocking-Johnson, D et al. (1995) Retention of glycoprotein Ib/IX receptors on external surfaces of thrombin-activated platelets in suspension. Blood 86:3468-78

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