Implications of C-peptide stimulated ATP release from red blood cells in autoimmune diseases
Adenosine triphosphate (ATP) is an energy containing molecule that is essential for numerous physiological processes throughout the body. ATP affects many different systems, such as the central nervous system, the immune system, and the vascular system. Due to ATP's vital role, alterations in its homeostasis can progress into several pathologies, such as type 1 diabetes (T1D) and multiple sclerosis (MS). Red blood cells (RBCs) play a fundamental role in blood flow regulation through indirectly stimulating vasodilation in the vasculature via secretion of ATP. As glucose levels rise within the circulation, GLUT1 activates in the RBC membrane, which propagates ATP release. This stimulates nitric oxide (NO) release from endothelial cells, which results in the relaxation of myosin filaments in the smooth muscle cells on the exterior of the vessel. This relaxation allows for vasodilation and increased blood flow through the vasculature. RBCs have numerous stimuli that result in ATP release and vasodilation, such as hypercapnia, hypoxia, deformation, and C-peptide. C-peptide is a molecule that is secreted by the pancreatic Îø-cell in response to high levels of glucose. C-peptide has been shown to increase metabolism within RBCs, by binding to RBCs, and stimulating an increase in ATP release. Individuals with T1D have been reported to have hypometabolic RBCs, corresponding to decreased C-peptide binding, GLUT1 activation and ATP release. Whereas individuals with MS have been reported to have hypermetabolic RBCs, corresponding to increased C-peptide binding, GLUT1 activation and ATP release. Understanding C-peptide's role in decreasing or increasing the metabolic activity of RBCs in both T1D and MS can provide vital information relating to the progression of these diseases and potential therapeutic sites of intervention.The work presented in this dissertation discusses the implications of C-peptide stimulated ATP release in T1D and MS. Methods to study this interaction utilize various binding techniques, as well as ATP measurements, to better understand how C-peptide plays a role in each disease state. These findings will aid in the determination of how these alterations may lead to the progression of T1D and MS, as well as, potentially unveiling novel therapeutic sites of intervention. An additional therapeutic mechanism of action in relation to C-peptide is outlined to determine if current therapies also affect C-peptide binding, transport and downstream physiologic effect on RBCs. The overall intent of the work in this dissertation is to discover and refine therapeutic interventions to improve the lives of individuals with T1D and MS.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- In Copyright
- Material Type
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Theses
- Authors
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Jacobs, Monica, 1996-
- Thesis Advisors
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Spence, Dana
- Committee Members
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Zinn, Kurt
McCabe, Laura
Langlois, Daniel
- Date Published
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2022
- Program of Study
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Comparative Medicine and Integrative Biology - Doctor of Philosophy
- Degree Level
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Doctoral
- Language
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English
- Pages
- xiv, 137 pages
- ISBN
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9798357565471
- Permalink
- https://doi.org/doi:10.25335/grz0-5k26