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Grant Abstract: Pathway maps of platelet phenotype and function

Grant Number: 5R01HL146549-02
PI Name: Aslan
Project Title: Pathway maps of platelet phenotype and function

Abstract: The consumption of plant-based foods and beverages enriched in flavonoids and other polyphenolic compounds is associated with better cardiovascular health. Despite increasing evidence for flavonoid containing dietary supplements in limiting metabolic syndrome, inflammation, thrombosis and other hallmarks of cardiovascular diseases, limited information is available regarding molecular mechanisms of flavonoid supplements as cardioprotective agents. The prenylated flavonoid xanthohumol (XN), isolated from the hops plant Humulus lupulus, is found in beer and has long been recognized as a bioactive molecule with potential medicinal and disease preventive properties. Our preliminary in vitro data suggests that XN targets specific molecular processes in blood platelets and alters intracellular signaling pathways to inhibit platelet reactivity in pro-inflammatory and pro-thrombotic contexts. The overall objective of this Administrative Supplement is to determine whether and how oral XN supplementation alters molecular programs in platelets to limit inflammatory and thrombotic platelet responses. Our central hypothesis is that XN supplementation alters platelet reactive oxygen species (ROS) generation as well as protein kinase C (PKC), mitogen-activated protein kinase (MAPK), PI3K/Akt and other systems to reprogram the platelet proteome in a manner limiting maladaptive phenotype transitions. As a major goal of the parent award is to determine how maladaptive platelet phenotypes develop, and, ultimately, how they may be targeted and managed, this work represents a unique opportunity to add value to ongoing studies while advancing supplement research with state-of-the-art methods. As a supplement to the parent award, this study will continue to make use of a high-throughput, proteomics-based workflow to measure and map intracellular signaling events in platelets isolated from subjects supplemented with XN or a placebo regimen. We will aim to systematically define how XN supplementation alters intracellular signaling events and other molecular processes that progress platelet adhesion (Aim 1), secretion (Aim 2) and aggregation (Aim 3) in the context of vascular inflammation and thrombus formation. Ultimately, this work will generate knowledge as well as a conceptual means to understand how flavonoid supplements reprogram platelets to limit disease.

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