Sickle cell disease is a genetic disorder that affects 100,000 Americans and millions more worldwide. Although the sickle mutation affects one protein, which is only expressed in a single cell type, it has profound detrimental effects on nearly every organ system in the body. Young children with sickle cell disease have an 11\% chance of suffering a major stroke event by the age of 16, and a 35\% chance of developing ÒsilentÓ strokes that often result in significant learning and mental disabilities. Clinical investigations suggest that stroke development in people with sickle cell disease results from luminal narrowing of the carotid and cerebral arteries due to excess matrix deposition and fragmentation of the elastic lamina; however, the underlying cellular mechanisms that initiate arterial remodeling in sickle cell disease remain relatively unknown. Cathepsins K and V are members of the cysteine family of proteases and represent two of the most potent elastases yet identified in humans. Furthermore, the role of Cathepsins has been well established in other cardiovascular remodeling diseases, such as atherosclerosis. Due to the compelling histological similarities between vasculopathy in sickle cell disease and atherosclerosis, we tested the hypothesis that the unique inflammatory milieu, in conjunction with the biomechanical vascular environment of sickle cell disease upregulates cathepsin K and V activity in large artery endothelial cells, ultimately leading to arterial remodeling and stroke. Currently, there are few therapeutic options for the prevention of stroke in sickle cell disease; those that do exist carry significant health risks and side effects. Together, this body of work has generated a more mechanistic understanding of how the sickle milieu stimulates the endothelium to initiate arterial remodeling, which has enabled us to identify important pathways (JNK, NF$\kappa$B) downstream of inflammatory and biomechanical stimuli and validate new therapeutic targets within the JNK pathway to establish preclinical proof of efficacy for the prevention of arterial remodeling in sickle cell disease.
| Identifer | oai:union.ndltd.org:GATECH/oai:smartech.gatech.edu:1853/54289 |
| Date | 07 January 2016 |
| Creators | Keegan, Philip Michael |
| Contributors | Platt, Manu O. |
| Publisher | Georgia Institute of Technology |
| Source Sets | Georgia Tech Electronic Thesis and Dissertation Archive |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
| Format | application/pdf |
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