Combinatorial Effect of Tyrosine Kinase and Calpain Inhibitors on Human Platelets
Abstract: Platelets play
a major role in the genesis, progression, morbidity, and mortality of cardiovascular
disease (CVD). As CVD progresses, fibrous plaques form along the arterial walls that
become progressively unstable. Sudden plaque rupture induces and contributes to the
development of both thrombosis and coagulation cascade resulting in lesions such as
acute myocardial infarction and/... read moreor ischemic strokes. Platelet glycoprotein GPIIb/IIIa,
also known as integrin αIIbβ3, plays an important role in mediating two
critical platelet processes: platelet activation and clot retraction. A diverse array of
proteins are involved in GPIIb/IIIa signaling. In this study, I investigated the
synergistic role of Src/Syk tyrosine kinases and calpain cysteine proteases in
regulating key platelet signaling cascades. By utilizing specific tyrosine kinase and
calpain inhibitors, we interrogated multiple signaling pathways including platelet
adhesion, spreading, and aggregation. Our results revealed a dual role of both Src/Syk
and calpain signaling pathways in platelet activation, and additive effects of the
combination of pharmacological inhibitors suggest a potential treatment modality for
preventing pathological thrombosis.
Thesis (M.S.)--Tufts University, 2017.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisors: Athar Chishti, and Andrew Bohm.
Keyword: Pharmacology.read less