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The main focus of the Becker lab has been on the mechanisms and consequences of post-ischemic myocardial inflammation.
Genomic control of platelet function:
Aggregation of blood platelets initiates clotting in coronary arteries, the main cause of heart attacks. Our laboratory conducts experiments to understand how genes control platelet function. Through funding by the National Heart Lung and Blood Institute, we have performed candidate gene analysis, linkage studies, whole genome association studies, and now whole genome sequencing in about 2000 healthy subjects from families with early onset coronary artery disease. The subjects are siblings or offspring of an individual identified with coronary artery disease before age 60 in the GeneSTAR Research Program (Genetic Studies of Atherosclerosis Risk). We have identified a large number of common and rare genetic variants associated with platelet aggregation, and although some variants are located in genes known to be important in... the biology of platelet function, most are in non-protein coding regions of genes (introns) or in intergenic regions of the genome. To understand better how these variants influence platelet function, we created pluripotent stem cells from blood mononuclear cells in 257 genotyped GeneSTAR subjects and then transformed the stem cells to megakaryocytes, the source of platelets in the bone marrow. We have determined the entire transcriptome of these megakaryocytes to measure gene expression levels in an effort to functionally link genetic variation with platelet function. We are also interested in epigenetic effects which regulate the amount of gene transcription and resulting protein formation. We have done similar transcriptomic and proteomic studies in blood platelets as we have in stem cell-derived megakaryocytes.
Our goal is to identify new therapeutic targets for drug development to control excessive platelet aggregation and reduce the risk of heart attack in susceptible individuals. We also hope to use the genetic information to predict who is at greatest risk for platelet aggregation or bleeding, and tailor treatment to effectively apply individualized precision medicine.
The Becker laboratory also extends its cardiovascular work well beyond platelet function, as noted on the GeneSTAR Research Program website. view less
Kelly Metcalf Pate Lab
The Kelly Metcalf Pate Lab focuses on the role of platelets in the innate immune response to viral infection, and how modulating the response of platelets to infection alters the course of disease.
Platelets are known to participate in innate immunity through cytokine signaling and direct interactions with other cells, and the platelet has the potential to significantly influence disease outcomes. However, platelet immunology is still a relatively new discipline, and the downstream effects of platelet interactions with other immune cells have yet to be determined in the context of viral infection.
Current research in our lab aims to further characterize the platelet-monocyte interaction during acute viral infection with the goals of establishing methods of pharmacologically manipulating this association, and establishing how platelet binding to a monocyte influences the monocyte's susceptibility to lentiviral infection and the monocyte's interactions with endothelium.
Additio...nally, we are interested in the effect of physiologic stress on the platelet's future immune response to infection, and in the development and optimization of novel in vitro systems that better model in vivo conditions.
Molecular and Comparative Pathobiology
Platelet Physiology Research Lab
Dr. Williams' research focuses on platelet physiology particularly as it relates to acute coronary syndromes and depression. Her laboratory specifically examines platelet aggregation, flow cytometric analysis to measure platelet activation, platelet luminescence as a measure of the platelet release reaction, many Elisa preparations in order to measure platelet function, platelet genotyping to determine the presence of certain platelet polymorphisms, and various other assays to distinguish mechanisms of platelet dysfunction. The goal for her cardiovascular platelet laboratory is to identify the etiology of platelet dysfunction in many disease states and apply methods that may improve this dysfunction that can eventually be translated to therapies for patients with cardiovascular disease. Scientific techniques performed in the lab include: flow cytometric analysis, platelet microparticle identification, and protein immunoprecipitation among other techniques.