Date of Award

2024

Degree Name

Biomedical Research

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Dr. Wei Li, Committee Chairperson

Second Advisor

Dr. Ji Bihl

Third Advisor

Dr. Adolfo Garcia-Sastre

Fourth Advisor

Dr. Ellen Thompson

Fifth Advisor

Dr. Hongwei Yu

Abstract

Thrombosis, as an underlying mechanism in cardiovascular diseases, is the leading global cause of death in the 21st century. Infection is a risk factor for thrombosis, and the coronavirus disease 2019 (COVID-19) pandemic has led to a rise in the incidence of thrombosis, thereby increasing mortality. In comparison to previous severe coronavirus outbreaks, rates of thrombosis in COVID-19 have been unprecedented. COVID-19 is caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 spike protein (SP), the key used to enter host cells, is implicated in thrombosis pathology, though mechanisms are not fully understood. The SARS-CoV-2 SP may also be involved in vaccine-induced immune thrombotic thrombocytopenia (VITT), a reaction to COVID-19 vaccination where deadly thromboses materialize. Discovering mechanism-based therapies for life-threatening diseases is paramount in minimizing off-target effects and maximizing positive responses to treatment. Thymidine phosphorylase (TYMP), a pyrimidine salvage pathway enzyme with novel prothrombotic function, has been identified by our lab as a target in COVID-19-associated thrombosis. This dissertation investigates SARS-CoV-2 SP-associated thrombosis using animal models, human tissue, blood studies, cell culture, and in-silico modeling, and shows the effectiveness of targeting TYMP to attenuate SP-promoted thrombosis. This dissertation aims to address knowledge gaps concerning the mechanistic impact of SP on thrombosis, establish a foundation for targeting TYMP as a potential therapeutic avenue, and unveil a novel interaction between SP and platelet factor 4 (PF4), which may bear implications for COVID-19-associated thrombosis and/or VITT.

Subject(s)

Cytology.

Molecular biology.

Thrombosis.

COVID-19 (Disease)

Cardiovascular system -- Diseases.

SARS (Disease)

Thrombocytopenia.

Phosphorylase.

Download

Share

COinS