Thromboembolic disease is a major cause of sudden death and catastrophic disability in Western societies. This grant will employ murine models of obesity to delineate underlying mechanisms. Preliminary Studies indicate that thrombi formed in ob/ob (leptin-deficient) and db/db (functional leptin receptor-deficient) mice in response to arterial injury (FeCI3) are unstable and frequently embolize. Administration of leptin stabilizes the thrombi formed in ob/ob but not in db/db mice, and promotes the aggregation of platelets from ob/ob but not db/db mice. The primary hypothesis of this grant is that leptin binds to its receptors on platelets, causing biochemical changes in platelet signaling and function that are necessary for thrombus stability.
In Aim 1, bone marrow transplantation studies and leptin and leptin inhibitor (e.g., neutralizing antibodies) infusion studies, will be performed to determine the origin, target, and kinetics of action of the stabilizing leptin in thrombi, and to test the hypothesis that decrease in leptin will lead to the formation of unstable thrombi in wild-type mice. The mechanism(s) by which leptin promotes thrombus stability and enhances platelet activation will be studied in Aim 2. The possibility that leptin is required for optimal platelet: platelet and/or platelet vessel wall interactions will be examined, and the effects of leptin and leptin inhibitors on the aggregation, secretion and signaling of murine platelets will be determined. Preliminary Studies show that leptin potentiates the aggregation of human platelets from some donors but not from others.
In Aim 3, the nature of the defect in non-responsive platelets (e.g., abnormalities in the leptin receptor) will be examined. The effects of leptin inhibitors on the aggregation of responsive and non-responsive platelets, and on the formation of stable """"""""thrombi"""""""" will be tested. These studies will provide novel insights into the unexpected role of leptin in platelet function, and in the formation and stability of thrombi.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL075736-01
Application #
6707461
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Ganguly, Pankaj
Project Start
2003-12-05
Project End
2007-11-30
Budget Start
2003-12-05
Budget End
2004-11-30
Support Year
1
Fiscal Year
2004
Total Cost
$469,250
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Heida, Nana-Maria; Leifheit-Nestler, Maren; Schroeter, Marco R et al. (2010) Leptin enhances the potency of circulating angiogenic cells via src kinase and integrin (alpha)vbeta5: implications for angiogenesis in human obesity. Arterioscler Thromb Vasc Biol 30:200-6
Neels, Jaap G; Badeanlou, Leylla; Hester, Kelly D et al. (2009) Keratinocyte-derived chemokine in obesity: expression, regulation, and role in adipose macrophage infiltration and glucose homeostasis. J Biol Chem 284:20692-8
Kamikubo, Yuichi; Dellas, Claudia; Loskutoff, David J et al. (2008) Contribution of leptin receptor N-linked glycans to leptin binding. Biochem J 410:595-604
Ruggeri, Zaverio M (2007) The role of von Willebrand factor in thrombus formation. Thromb Res 120 Suppl 1:S5-9
Dellas, Claudia; Schafer, Katrin; Rohm, Ilonka K et al. (2007) Leptin signalling and leptin-mediated activation of human platelets: importance of JAK2 and the phospholipases Cgamma2 and A2. Thromb Haemost 98:1063-71
Konstantinides, S; Ware, J; Marchese, P et al. (2006) Distinct antithrombotic consequences of platelet glycoprotein Ibalpha and VI deficiency in a mouse model of arterial thrombosis. J Thromb Haemost 4:2014-21
Konstantinides, Stavros; Schafer, Katrin; Neels, Jaap G et al. (2004) Inhibition of endogenous leptin protects mice from arterial and venous thrombosis. Arterioscler Thromb Vasc Biol 24:2196-201