Novel signaling molecules regulating platelet activation

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The purpose of this Research Supplement to Promote Diversity in Health-Related Research is to support a project of the applicant which is an extension of the research parent R35 grant. The applicant is Haitian American citizen and a member of the Black underrepresented minority group. Platelets play a crucial role in hemostasis and thrombosis, and more and more studies indicate their role in other disease states including inflammation, cancer, and atherosclerosis. The R35 focuses on these signaling steps and how their interplay mediates platelet activation. Understanding signaling networks and their regulation has been my research focus for the past two decades and our group has made important contributions to the platelet-signaling field. The goal of the R35 is to identify novel signaling molecules that regulate main signaling pathways, characterize novel signaling pathways emanating from the same signaling molecule, and understand the differences in various tyrosine kinase pathways in platelets. The research design for the supplement grant follows the original studies constituting the parent grant and will be focused on research discovering novel signaling mechanisms provided by structures within bacterial biofilms which can increase platelet activation. Enterococcal septicemia, predominantly caused by E. faecalis, can be difficult to treat with antibiotics and lethality approaches 25% of patients if the infection is not resolved in 30 days. This lethality rate is significantly higher than S. aureus, and the basis of the increased mortality is not known. Not all E. faecalis blood stream infections lead to septicemia suggesting there may be strain to strain variation. E. faecalis strains range from ubiquitous commensals of the gastrointestinal tract to multidrug resistant nosocomial pathogens. Mobile genetic elements play an important role in converting commensal E. faecalis into nosocomial multidrug resistant (MDR) opportunistic pathogens. Pheromone responsive plasmids can be present in >60% of characterized pathogenic isolates and are correlated with increased size of heart vegetations in endocarditis rabbit models by unknown mechanisms. During the applicant's master studies in a basic bacteriology laboratory, the applicant discovered the plasmid pCF10 remodeling the E. faecalis biofilm producing densely packed rigid structures within viscous surface-attached biofilms and lead to the production of nonattached biofilm aggregates containing viscous biofilms with rigid structures. For the Ph.D. the applicant wants to do biomedical research including animal modeling and human platelets. The central hypothesis is that rigid structures in biofilms and biofilm aggregates, activate platelets by three unique mechanisms, tugging effects of multiple sites on the glycoprotein Ib/V/IX to generate thromboxane A2 (Aim 1) and PKC for platelet activation and Y155 phosphorylation for inflammation will both contribute to increasing thrombotic risk leading to sepsis in animals infected with plasmid-containing strains (Aim 2). Completion of this project will aid the candidate in establishing a career in biomedical disease research and, with an interest in education, the candidate will serve as a role model for further recruitment and training of URM scientists.