Save kidneys in cisplatin chemotherapy by blocking HDAC6
Active Project Grant Awarded Last action
- Award ID
- R01DK142969
- Recipient
-
Rhode Island Hospital UEI N876TLXYGCG4
- Awarding agency
-
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $1,961,546
Award facts
- Assistance listing
- 93.847 Diabetes, Digestive, and Kidney Diseases Extramural Research
- Completion date 25% complete
- Place of performance
- Providence, RI 02903, USA
Award details come from USAspending.gov.
Description
- Abstract
- Cisplatin and its derivatives are the most widely used chemotherapeutic agents for treating solid tumors. However, cisplatin induces kidney injury during its use in cancer therapy. Currently, no treatment is available for cisplatin-induced kidney injury except supportive care. The goal of this project is to elucidate the role and mechanism of histone deacetylase 6 (HDAC6) in cisplatin-induced kidney injury, fibrosis and chronic kidney disease (CKD), and to identify HDAC6 inhibition as a novel approach for renoprotection during cancer treatment. In our preliminary studies, HDAC6 was up-regulated in acute kidney injury (AKI) induced by a single high-dose of cisplatin in mice and pharmacological inhibition of HDAC6 attenuated renal tubular apoptosis and AKI. HDAC6 was also highly induced by repeated low-dose cisplatin (RLDC) treatment, which was accompanied by renal interstitial fibrosis, persistent activation of epidermal growth factor receptor (EGFR) and autophagy, and deacetylation of Α-tubulin, a key process in cilium disassembly. Importantly, pharmacological and genetic blockade of HDAC6 reduced RLDC-induced renal fibrosis. Moreover, cisplatin treatment induced shortening of primary cilium in cultured renal epithelial cells, and the cells with shorter cilia were more sensitive to cisplatin-induced injury. These data, together with a known cancer-promoting role of HDAC6 in tumors, have led to our hypothesis that blockade of HDAC6 may protect kidneys during cisplatin chemotherapy while enhancing its anti-cancer efficacy in tumors. Mechanistically, HDAC6 may contribute to the development of chronic kidney problems after cisplatin treatment through the activation of EGFR and autophagy, and disassembly of primary cilium in renal tubular cells. We propose three specific aims to (1) test the hypothesis that HDAC6 can protect kidneys during cisplatin treatment while enhancing the chemotherapy effects in tumors; (2) test the hypothesis that HDAC6 contributes to cisplatin-induced renal injury, fibrosis and CKD by persistent activation of EGFR and autophagy; and (3) test the hypothesis that HDAC6-mediated ciliary disassembly aggravates kidney injury, fibrosis and CKD following cisplatin treatment. Successful completion of the proposed studies will define the therapeutic effect of HDAC6 inhibition on cisplatin-induced renal damage and fibrosis, elucidate the underlying mechanisms, and identify a novel strategy for kidney protection while enhancing chemotherapeutic efficacy.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $643,182 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $659,182 | |
| Original award | $659,182 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Augusta University | $245,361 | |
| Augusta University | $245,361 |
Quick answers
Who received award R01DK142969?
R01DK142969 was awarded to Rhode Island Hospital by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on September 8, 2025.
How much is award R01DK142969 worth?
$1,961,546 has been obligated on R01DK142969.
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