Cargill, Kasey
(2019)
The Role of Hypoxia in Metabolism and Nephron Development.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Self-renewing cell populations, such as stem and cancer cells, are highly metabolically active and proliferate by up regulating glycolytic metabolism. Nephron progenitors—which give rise to nephrons—are particularly metabolically active and similarly rely on the glycolysis pathway to drive proliferation. Conversely, as nephron progenitors mature they switch to mitochondrial oxidative phosphorylation coinciding with loss of stemness and rapid differentiation. The mechanism driving this metabolic switch and subsequent differentiation is currently unknown. Oxygenation is an important developmental process tightly regulated by several oxygen-dependent molecules. Although the kidney develops in a relatively hypoxic environment, as the renal vasculature matures, oxygen tension increases. The major hypoxia- responsive pathway expressed in the developing kidney allows for the recruitment of the ubiquitin ligase von Hippel Lindau (VHL) to mark the transcription factor hypoxia-inducible factor 1α (HIF-1α) for proteasomal degradation, a process that we hypothesize leads to normal nephron progenitor differentiation. Prolonged hypoxic insult however, interrupts this pathway such that HIF-1α remains stabilized and continues activation of genes involved in cellular processes including angiogenesis, cell cycle regulation, and metabolism. This investigation reveals a previously unknown mechanism controlling the balance between nephron progenitor self-renewal and differentiation. Collectively, this study found that hypoxia and the VHL/HIF pathway play a critical role in this process by mediating the metabolic switch that is required for nephron progenitor differentiation.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
26 September 2019 |
| Date Type: |
Publication |
| Defense Date: |
12 July 2019 |
| Approval Date: |
26 September 2019 |
| Submission Date: |
1 August 2019 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
185 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Genetics and Developmental Biology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Kidney development, Hypoxia, Nephron, VHL, HIF, Metabolism |
| Date Deposited: |
26 Sep 2019 13:49 |
| Last Modified: |
26 Sep 2019 13:49 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/37240 |
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