The foremost cause of death in humans is cardiovascular diseases such as myocardial infarction and stroke. Circulating platelets play an important role in the pathogenesis of these diseases. Platelets are anucleated cells with a complex cytoskeletal system, unique receptors, and specialized secretary granules. They are found in the circulation in high abundance, and respond to blood vessel injury by changing shape, secreting granular contents, and aggregation. This is advantageous in the regulation of physiological hemostasis, but can be unfavorable in pathological thrombosis. For this reason, understanding the mechanisms surrounding platelet aggregation is essential. Platelet function is tightly regulated by both pro- and anti-stimulatory mechanisms. 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 platelet protein, ASK1, which appears to be a key participant in the pro-stimulatory mechanism. We hypothesize that ASK1 senses stress and/or pro-stimulatory signals initiated by agonists and transmits signals to the platelet fibrinogen receptor complex and helps in coordinating stimulatory signals that regulate platelet aggregation and thrombus formation. This proposal is focused on understanding the molecular mechanisms that are regulated by ASK1 in order to regulate platelet activation. The identification and characterization of such regulatory mechanisms may define new targets for developing potential therapeutic agents toward thrombotic disorders.
Regulation of platelet aggregation is paramount in achieving hemostasis and controlling thrombosis. Unwanted diversion from this regulation may result in life-threatening pathological conditions such as myocardial infarction and stroke. Full understanding of these processes and identification of novel intermediate signaling events/players may help in developing new therapeutic strategies to overcome these pathological conditions. The proposed research has potential to identify such targets that regulates platelet functions.
|Patel, P; Golla, K; Naik, U P (2018) PDK1 governs thromboxane generation and thrombosis in platelets by regulating activation of Raf1 in the MAPK pathway: comment. J Thromb Haemost 16:1901-1904|
|Naik, Meghna U; Patel, Pravin; Derstine, Randall et al. (2017) Ask1 regulates murine platelet granule secretion, thromboxane A2 generation, and thrombus formation. Blood 129:1197-1209|
|Naik, Meghna U; Naik, Tejal U; Summer, Ross et al. (2017) Binding of CIB1 to the ?IIb tail of ?IIb?3 is required for FAK recruitment and activation in platelets. PLoS One 12:e0176602|
|Yoon, Kyoung Wan; Yang, Hyun-Suk; Kim, Young Mok et al. (2017) CIB1 protects against MPTP-induced neurotoxicity through inhibiting ASK1. Sci Rep 7:12178|
|Kraft, W K; Gilmartin, J H; Chappell, D L et al. (2016) Effect of Vorapaxar Alone and in Combination with Aspirin on Bleeding Time and Platelet Aggregation in Healthy Adult Subjects. Clin Transl Sci 9:221-7|
|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|