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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-VH-J (02))
Program Officer
Kindzelski, Andrei L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Delaware
Schools of Arts and Sciences
United States
Zip Code
Lathia, Justin D; Li, Meizhang; Sinyuk, Maksim et al. (2014) High-throughput flow cytometry screening reveals a role for junctional adhesion molecule a as a cancer stem cell maintenance factor. Cell Rep 6:117-29
Naik, Meghna U; Caplan, Jeffrey L; Naik, Ulhas P (2014) Junctional adhesion molecule-A suppresses platelet integrin *IIb*3 signaling by recruiting Csk to the integrin-c-Src complex. Blood 123:1393-402
Chatterjee, Sharmila; Wang, Yan; Duncan, Melinda K et al. (2013) Junctional adhesion molecule-A regulates vascular endothelial growth factor receptor-2 signaling-dependent mouse corneal wound healing. PLoS One 8:e63674
Naik, Meghna U; Stalker, Timothy J; Brass, Lawrence F et al. (2012) JAM-A protects from thrombosis by suppressing integrin αIIbβ3-dependent outside-in signaling in platelets. Blood 119:3352-60
Lakshmi, Sowmya P; Reddy, Aravind T; Naik, Meghna U et al. (2012) Effects of JAM-A deficiency or blocking antibodies on neutrophil migration and lung injury in a murine model of ALI. Am J Physiol Lung Cell Mol Physiol 303:L758-66
Aravindan, Rolands G; Fomin, Victor P; Naik, Ulhas P et al. (2012) CASK interacts with PMCA4b and JAM-A on the mouse sperm flagellum to regulate Ca2+ homeostasis and motility. J Cell Physiol 227:3138-50