Platelets are anucleated cells found in abundance in circulation and play an important role in the process of physiological hemostasis. However, unwanted platelet activation results in a pathological condition termed thrombosis, which is the root cause of major cardiovascular diseases such as myocardial infarction and stroke. During vascular injury, circulating platelets adhere to the exposed subendothelial proteins such as collagen and are activated. Activated platelets recruit more platelets by secreting ADP from their granules and by generation of thromboxane A2. Activated platelets form a stable plug through fibrinogen-dependent crosslinking of integrin ?IIb?3. This process is tightly regulated and any defect in this regulation can result in impaired platelet activation resulting in bleeding disorder. For this reason, understanding the mechanisms surrounding platelet activation is essential. Platelets are kept in an unstimulated state by little-known anti-stimulatory mechanisms. During vascular injury, pro-stimulatory mechanisms, such as signaling by various physiological agonists, override the anti-stimulatory machinery to achieve platelet aggregation. We have identified a novel protein named JAM-A, which is expressed on platelets and negatively regulates platelet function. JAM-A binds to integrin ?IIb?3 and suppresses its activation and signaling. How the interaction of JAM-A with the integrin affects platelet function is not well understood and is the focus of this proposed application. We hypothesize that JAM-A is an endogenous inhibitor of integrin activation, and affects integrin outside in signaling. To test thi hypothesis, we will use Jam-A knockout mice and evaluate the molecular mechanisms through which JAM-A suppresses platelet activation and thus thrombosis.
Understanding the molecular mechanism of regulation of platelet activation is paramount for developing therapeutic interventions to combat thrombotic disorders. JAM-A, an endogenous suppresser of this process, may provide important cues in understanding this mechanism.
