Myers, Tracey Danielle
(2024)
Investigation of Pathological Processes in a Novel Murine Model of Triosephosphate Isomerase Deficiency and Assessment of Potential Therapeutics.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Triosephosphate isomerase deficiency (TPI Df) is an exceedingly rare disorder that results in a severe disease course which strongly affects the neuromuscular system among other systems. Patients typically die in early childhood, and currently there are no treatments for the disease. Previous studies into the pathogenesis of TPI Df have relied on invertebrate models or in vitro experimentation due to the lack of higher-order disease models. This work focuses on the creation and detailed characterization of the first mammalian model of TPI Df. The most common disease-causing mutation, a glutamic acid to aspartic acid substitution in the 105th codon of the TPI1 gene (TPI1[E105D]), was modeled within the mouse. TPI protein is involved in the 5th step of the glycolytic pathway and is ubiquitously expressed. Introduction of the TPI1[E105D] mutation results in a protein with highly reduced stability, resulting in low levels of protein that lead to progressive multi-system dysfunction. Modeling TPI Df with this mutation in the mouse resulted in severe phenotypes that effectively recapitulated symptoms seen in TPI Df patients. Tpi1[E105D/null] mice display neurodegeneration in the central nervous system, alterations in the function of motor neurons, dysfunction in all three kinds of muscle, and severe hemolytic anemia, together contributing to a severe reduction in lifespan. Mice carrying homozygous Tpi1[E105D/E105D] mutations also present with strong phenotypes, though generally they are less severe than Tpi1[E105D/null] animals as expected. Homozygous Tpi1[E105D/E105D] animals were used to assess two lead compounds identified through high-throughput drug screening in cell culture models, resveratrol and pitavastatin, for efficacy in the treatment of TPI Df. Neither resveratrol nor pitavastatin were able to rescue disease phenotypes at the dosing paradigms assessed. Moving forward, this novel murine model will prove useful for mechanistic studies of TPI Df and establishes a mammalian model in which novel therapeutic strategies can be assessed before moving into human studies.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
27 September 2024 |
| Date Type: |
Publication |
| Defense Date: |
4 April 2024 |
| Approval Date: |
27 September 2024 |
| Submission Date: |
30 April 2024 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
171 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Neurodegenerative Disease
Neuromuscular Disease
Neuropharmacology
Glycolytic Enzyme
Protein Quality Control
Clinical History
Rare Disease |
| Date Deposited: |
27 Sep 2024 15:31 |
| Last Modified: |
27 Sep 2024 15:31 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46360 |
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