Date of Graduation

2015

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Neurology

Committee Chair

Taura L Barr

Committee Co-Chair

Paul D Chantler

Committee Member

Stanley M Hileman

Committee Member

Gregory Konat

Committee Member

James W Simpkins

Abstract

Acute ischemic stroke (AIS) is currently the fifth leading cause of death and a leading cause of long-term disability in the United States. Further, the incidence of AIS is expected to increase dramatically through year 2030. Despite the current and anticipated burden of AIS, treatment options for AIS, both acute and chronic, are extremely limited. Tissue plasminogen activator (tPA) is currently the only FDA-approved drug used to treat AIS; however, only a small fraction of AIS patients are eligible to receive tPA, and of these, only roughly 15 percent benefit from treatment with tPA. Given this, there is a crucial need to develop novel therapeutic options for AIS that may act independently or improve the efficacy of tPA. The use of human biomarker studies has led to the discovery of several biomarkers that can be used to diagnose AIS from other pathological conditions and can also be used to identify therapeutic targets for future therapeutics. Our laboratory has previously identified arginase 1 (ARG1) as the most significantly upregulated gene in the blood of AIS patients compared to control; however, the source and functional significance of this elevation is unclear. ARG1 has been shown to have a broad range of functions, including mediating the immune system response and vascular function, and because changes in both immune and vascular function play a role in AIS severity and recovery, ARG1 may represent a novel prognostic marker and therapeutic target in AIS.;The purpose of this dissertation was to better characterize the role of ARG1 in AIS and cardiovascular disease (CVD) as a whole. Specifically, to determine how changes in ARG1 expression may mediate immune function and vascular function, and how these alterations impact disease incidence, progression, and recovery. Herein, we have shown that increased ARG1 expression is associated with changes in immune function that may contribute to post-stroke immunosuppression and poor recovery following AIS. Further, in addition to mediating the immune response to AIS, increased ARG1 is also associated with increased arterial stiffness and vascular dysfunction following AIS. Lastly, we have shown that increased ARG1 expression is associated with vascular dysfunction outside of AIS, in the context of patients with CVD risk factors. Our results suggest a potential role for ARG1, as both a diagnostic and prognostic marker in AIS. We also have evocative evidence to suggest that ARG1 inhibition may be a potential therapeutic strategy to reduce the incidence and severity of AIS.

Download

Share

COinS