Advisors: 

Manu O. Platt, Ph.D. (Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech)

Edward A. Botchwey, Ph.D. (Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech)

Committee Members:

Spencer H. Bryngelson, Ph.D. (School of Computational Science and Engineering, Georgia Tech)

Rudolph L. Gleason, Ph.D. (George W. Woodruff School of Mechanical Engineering, Joint Appointment in the School of Biomedical Engineering, Georgia Tech)

John N. Oshinski, Ph.D. (Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech & Emory University)

Alessandro Veneziani, Ph.D. (Department of Mathematics, Emory University)

Longitudinal Magnetic Resonance Angiography to Quantify Arterial Remodeling in Sickle Cell Disease

Sickle cell disease (SCD) is a devastating inherited blood disorder associated with progressive arterial damage and a heightened stroke risk, particularly ischemic stroke in childhood and hemorrhagic stroke in early adulthood. The mechanisms driving arterial damage in SCD are still not fully understood. In clinical settings, magnetic resonance angiography (MRA) has become indispensable for evaluating cerebrovascular health and stroke management. While bone marrow transplantation (BMT) is the only curative therapy for SCD, some individuals remain at risk for stroke post-transplant, underscoring the need for optimized timing to prevent arterial complications. 

Using a humanized SCD mouse model, we performed non-contrast MRA to investigate arteriopathy by measuring common carotid artery luminal areas longitudinally. SCD mice exhibited expansive outward remodeling with age, indicating a weakened arterial wall. In addition, MRA revealed large artery abnormalities, including stenoses and occlusions in carotid and cerebral arteries, mirroring findings in SCD patients with stroke complications. To identify imaging biomarkers for early detection, we applied radiomics analysis to MRA images, distinguishing SCD from heterozygous mice based on quantitative radiomic features. We further optimized phase contrast-MRI methods for blood flow measurements in the common carotid arteries of SCD mice. In addition, we established a method for computational fluid dynamic modeling to evaluate the relation between common carotid artery geometries obtained from MRAs and hemodynamics. 

To explore potential therapeutic strategies, we investigated the role of cathepsin K, a potent collagenase and elastase upregulated in SCD, in arterial remodeling. Genetic knockout of cathepsin K in SCD mice mitigated expansive remodeling, medial thinning, and elastin and collagen degradation in the arterial wall. Finally, we assessed whether BMT could prevent arterial remodeling in SCD mice at different disease stages. Early BMT at 2 months prevented arterial remodeling, whereas late BMT at 4 months failed to reverse pre-existing damage. These results emphasize the importance of early intervention to prevent irreversible arterial damage in SCD. As the field continues to advance with gene-editing therapies, this work may provide valuable guidance on optimizing the timing of intervention to maximize the benefits of these innovative treatments.