Our research centers on the molecular pharmacology and physiology of nucleotide receptors in the cardiovascular system, with a particular emphasis on the molecular mechanisms of ADP-induced platelet activation.  

We have identified three nucleotide receptors on platelets and successfully cloned the P2Y1 receptor, which couples to activation of phospholipase C from a platelet library. Our work has shown that the P2Y1 receptor plays an essential role in the ADP-induced platelet shape change and aggregation. 

Our long-term objectives are to delineate the signal transduction pathways linked to all three nucleotide receptors, identify the ligand binding sites on the P2Y1 receptor, clone the P2Y12 receptor associated with inhibition of adenylyl cyclase, and characterize the desensitization mechanisms of the P2Y receptors in platelets.  

We are also investigating downstream signaling events and focusing on the receptor domains that couple to G proteins and their ligands.  

Within the broader field of platelet signaling, our studies extend to pathways activated by GPVI and CLEC-2, which converge on Syk and PLC. Here, we are particularly interested in how Syk is regulated through phosphorylation and its role as a nodal point for signaling diversity. 

Seeing patients with inherited platelet bleeding disorders is not uncommon in clinical practice. However, in the vast majority, the underlying molecular mechanisms leading to platelet dysfunction are unknown.  

Our studies have focused on platelet signaling processes in these patients and have delineated hitherto undescribed abnormalities in key signaling proteins, including phospholipase C-beta-2, GTP binding protein G-alpha-q and protein kinase-C-theta. The insights from these studies will lead to better understanding of normal platelet mechanisms and the identification of novel targets to develop newer antiplatelet agents.  

Other research focuses on the anti-platelet drugs aspirin, clopidogrel and cilostazol, which are widely used in the management of patients with Peripheral Arterial Disease. However, the effects of these agents when used in combination on platelet function and the blood coagulation system have not been clarified.  

Our work seeks to define these effects, including on the tissue factor pathway of blood coagulation. Our studies suggest that anti-platelet agents inhibit circulating levels of tissue factor, a mechanism not previously recognized. This is likely to contribute to the anti-thrombotic effects of these agents. 

Our interdisciplinary research investigates how structural arrangements of bacterial biofilms influence their behavior and, antibiotic resistance, as well as their role in disease. We combine biological experiments with computational modeling and machine learning to predict bacterial behavior and recognize structural patterns, using several discrete approaches.  

1. We study how pheromone-responsive plasmids remodel viscous low-density commensal Enterococcus faecalis biofilms to form complex rigid structures, increase antibiotic resistance and affect the activation of neutrophils and thrombocytes to increase severity of endocarditis and septicemia. We are developing predictive models that integrate machine learning and simulation to identify antibiotic-protective patterns across biofilms from medical, environmental and industrial sources.  

2. We are building machine learning tools to identify interdependent bacterial subcommunities in the human microbiome that may influence systemic inflammation and thrombotic risk. To develop the tools, we use subaerial biofilm communities on marble monuments. In this simplified model system, cyanobacteria provide carbon and other bacterial subcommunities provide essential processes such as water retention, pH buffering and nitrogen supply.  

3. In collaboration with the Center for Biofilm Engineering at Montana State University, we are establishing a Biofilm Imaging Library to collect images that span medical, environmental and industrial biofilms to support the advancement of machine-learning-based biofilm discovery tools. 

Our research focuses on uncovering the molecular and cellular mechanisms underlying heart failure, a major clinical challenge marked by high morbidity and mortality. We study how inflammatory and coagulation-related proteases influence key signaling pathways that control cardiac cell growth, survival and death. These molecules are key mediators of cardiac stress responses and hold promise as potential biomarkers and therapeutic targets.  

A significant area of our work addresses the specific developmental pathways active during heart formation that remain functional shortly after birth and may be harnessed to promote cardiac repair and regeneration in adults.  

We are also investigating the role of protease-activated receptor 4 (PAR4) beyond its known function in coagulation, evaluating how PAR4 modulates cardiac inflammation, healing and remodeling. In parallel, we study the link between heart failure and cognitive decline, examining how cardiac injury alters gene expression in the brain independently of hemodynamic dysfunction.  

Our experimental approach integrates in vitro gain- and loss-of-function strategies with in vivo studies using genetically engineered mouse models that selectively manipulate candidate molecules in the heart. These models allow us to dissect disease-related signaling networks and evaluate therapeutic strategies under physiologically relevant conditions.

Our major goal is to determine how TMX1, a transmembrane member of the Protein Disulfide Isomerase (PDI) family, negatively regulates platelet function and coagulation to reduce thrombosis. To this end, we combine a platelet-specific knockout mouse model of platelet dysfunction with mass spectrometry-based identification of functional cysteine residues. We are determining how TMX1 activity interacts with the function of the prothrombotic members of the PDI family: PDI, ERp57, ERp72 and ERp46.  

Our overall goal is to characterize the substrates and functions of these vascular thiol isomerases, while learning how the redox network they form supports hemostasis and thrombosis.