Differences in the African American and European American Platelet Transcriptomes Alter Platelet Function and May Contribute to Racial Disparities in Cardiovascular Disease and Cancer

The primary role of platelets is their function in wound healing and hemostasis. During normal platelet activation, surface glycoproteins will bind to collagen and other molecules exposed from damaged blood vessels. This initiates a signal cascade within the platelet, culminating in platelet aggregation and, eventually, blood clot formation. When platelet activity becomes dysregulated, aberrant clot formation can lead to various forms of cardiovascular disease (CVD), the leading cause of death in the United States. Despite reductions in premature in European American (EA) CVD death rates, African American (AA) CVD death rates are considerably higher and have remained stagnant for decades. Additionally, AA platelets are inherently more active than EA platelets. Several studies have identified specific platelet genes dysregulated in AA platelets that are associated with increased CVD risk. In the following studies, we sought to identify global differences in platelet gene expression and alternative gene splicing between AA and EA platelets. We identified several differentially expressed or spliced genes within key pathways of platelet regulation, including calcium mobilization, integrin signaling, thrombin signaling, and ERK/MAPK signaling.While circulating throughout the bloodstream, platelets interact with other cells, including circulating tumor cells (CTCs). Bidirectional signaling between platelets and CTCs activates platelets and increases cancer cell oncogenicity. In this dissertation we aimed to further characterize the interactions between platelets and prostate cancer (PCa). We show that PCa cells stimulate calcium mobilization and surface expression of activated-platelet markers in platelets, and that platelets increase invasion and apoptotic resistance in PCa cells. Additionally, we used RNA-Seq, to identify several signaling axes potentially involved in these interactions, including integrin αIIbβ3-FN1, integrin αIIbβ3-ADGRE5, ephrin-EPH receptor, and LPA-LPAR, and evaluated their function in this crosstalk. Additionally, we examine platelet-like particles (PLPs), a common model used in platelet studies whose similarities to platelets have not been fully explored. Here we show the many genomic and functional differences between platelets and this model, bringing into question their usefulness as an in vitro substitute for platelets. The studies in this dissertation aim to elucidate the mechanisms behind platelet activity and its relation to platelet-related diseases. Furthermore, we anticipate it will serve to aid in the development of novel therapeutics for both CVD and cancer, especially in AAs who are at higher risk of these diseases.

Author

• Garofano, Kaitlin

Language

• en

Keyword

• Platelet-Like Particles
• Platelets
• Genomics
• Prostate Cancer
• Racial Disparities
• Alternative Splicing

Date created

• 2022

Type of Work

• Dissertation

License

• All rights reserved

Rights statement

• In Copyright

GW Unit

• Molecular Medicine

Degree

• Ph.D.

Advisor

• Lee, Norman H

Committee Member(s)

• O'Brien, Travis
• Horvath, Anelia
• Chiappinelli, Katherine

Persistent URL

•  https://scholarspace.library.gwu.edu/etd/7s75dd24c