Please use this identifier to cite or link to this item:
http://hdl.handle.net/11375/22061
Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | Hawke, Thomas | - |
dc.contributor.author | Rebalka, Irena Alexandra | - |
dc.date.accessioned | 2017-10-04T19:40:09Z | - |
dc.date.available | 2017-10-04T19:40:09Z | - |
dc.date.issued | 2017-11 | - |
dc.identifier.uri | http://hdl.handle.net/11375/22061 | - |
dc.description.abstract | Type 1 diabetic (T1D) individuals are burdened with many systemic complications, including impairments in skeletal muscle and cutaneous repair following injury. Plasminogen activator inhibitor 1 (PAI-1), the primary inhibitor of the fibrinolytic system, plays a critical role in the regulation and progression of tissue repair via controlling both extracellular matrix breakdown and cell migration. Previous work has demonstrated that elevations in PAI-1 inhibit adequate tissue regeneration, and has shown that PAI-1 is overexpressed in T1D patients regardless of insulin therapy. As such, the purpose of this thesis is to investigate the effects of known PAI-1 inhibitors on tissue repair of skin and skeletal muscle in T1D. To undertake these experiments, a rodent model of T1D was used, and animals were subject to cutaneous and skeletal muscle injuries. PAI-039, a small-molecule PAI-1 inhibitor, and Fluvastatin, a readily available statin that, among other functions, is known to inhibit PAI-1, were administered, and their effects on tissue regeneration were examined. PAI-039 was effective in restoring cutaneous wound closure in T1D. Fluvastatin, on the other hand, not only proved deleterious to both cutaneous and skeletal muscle regeneration, but also caused a pathological change in lipid deposition in the diabetic rodents. Overall, PAI-1 inhibition via a therapeutic agent that has a multitude of other pleiotropic effects is not recommended for improving T1D tissue repair. PAI-1 inhibition via a specific small-molecule inhibitor does, however, prove beneficial to cutaneous regeneration. Taken together, this data lays the foundation for future studies investigating small-molecule PAI-1 inhibitors as a therapeutic for the restoration of tissue repair in T1D. | en_US |
dc.language.iso | en | en_US |
dc.title | The inhibition of PAI-1 for restoration of skeletal muscle and skin repair in diabetes mellitus | en_US |
dc.type | Thesis | en_US |
dc.contributor.department | Medical Sciences | en_US |
dc.description.degreetype | Thesis | en_US |
dc.description.degree | Doctor of Philosophy (PhD) | en_US |
dc.description.layabstract | Type 1 diabetes is a lifelong condition that affects many of the normal functions of the body. Type 1 diabetic patients have an impaired ability to heal wounds on their skin and repair muscle after damage or exercise, greatly affecting their quality of life. One factor other than blood sugar that is found in abnormally high levels in diabetic patients is PAI-1, which inhibits proper movement of cells and healing of wounds. In this thesis, we investigated the effects of PAI-1 inhibition on tissue repair in diabetic rodents. While a specific therapeutic designed only to inhibit PAI-1 helped skin wounds close, a commercially available drug that has been shown to inhibit PAI-1 as a secondary effect made healing of diabetic skin and muscle worse. The findings in this body of work suggest that specialized PAI-1 inhibitors should be further investigated as a therapeutic to help restore diabetic tissue repair. | en_US |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
Rebalka_Irena_A_2017September_PhD.pdf | 9.81 MB | Adobe PDF | View/Open |
Items in MacSphere are protected by copyright, with all rights reserved, unless otherwise indicated.