Han, Hwa
(2020)
Slow and Steady: 4-Phenylthiobutanoic Acid Inhibits Histone Deacetylase 8 to Enhance Post-Acute Kidney Injury Repair.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Acute kidney injury (AKI) is a rapid decline in kidney function that is associated with high mortality and morbidity rates, affecting 1 in 5 adults worldwide 1. While damaged renal tubular epithelial cells (RTECs) undergo reparative process to proliferate and replace the damaged epithelium, it is not a robust mechanism. The initial damage is followed by a cross-talk of innate immune system and RTECs resulting in exacerbation of inflammation, fibrosis, and sometimes irreversible damage. Despite the prevalence and severity of AKI, no FDA approved therapeutics exist to replace damaged or lost RTECS. Therefore, it is imperative to screen, identify, and understand mechanisms with which candidate therapeutics can enhance repair. Our group identified 4-phenylthiobutanoic acid (PTBA) and developed analogs to enhance renal repair when treated post-AKI. However, the protein target(s) as well as the mechanisms responsible for enhanced recovery are not completely understood. Here, we used a zebrafish larvae AKI model to visualize RTEC cellular response during PTBA treatment. We also characterized the zebrafish immune response during AKI and the effect of PTBA on modulating the innate immune cell response. Lastly, we used in vivo and in vitro methods to identify the target of PTBA, Histone deacetylase 8 (HDAC8). Using knockout hdac8 (hdac8-/-) zebrafish, we showed a similarly enhanced recovery of hdac8-/- as we saw in animals treated with PTBA. We further demonstrated the hdac8-/- show changes cell cycle dynamics and epithelial to mesenchymal transition. Taken together, our work provides another step forward in pro-regenerative compound development.
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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Unpublished |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: |
21 September 2020 |
| Date Type: |
Publication |
| Defense Date: |
29 May 2020 |
| Approval Date: |
21 September 2020 |
| Submission Date: |
1 August 2020 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
154 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Developmental Biology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Acute kidney injury, Histone deacetylase inhibitor, Cell cycle, Zebrafish, Kidney repair |
| Date Deposited: |
21 Sep 2020 15:24 |
| Last Modified: |
21 Sep 2020 15:24 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/39475 |
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