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Role of the MUC1/HIF-1a Complex in the kidney proximal tubule during ischemia-reperfusion injury.

Award Number: R03DK131093
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Abstract. Acute kidney injury (AKI) is a common and devastating clinical problem. Despite the morbidity, mortality, and financial drain associated, there are no established therapies outside of dialytic treatment. Recent work has identified adaptive responses in the tubular epithelium to cope with ischemia-reperfusion injury (IRI). There is a critical need to identify how adaptive responses are regulated in AKI so that therapeutic interventions to prevent and treat AKI can be developed. Hypoxia inducible factor-1 (HIF-1) is a transcription factor regarded as the most significant mediator of cellular adaptive responses to hypoxic insult. There is emerging evidence that the transmembrane glycoprotein mucin 1 (MUC1) expressed on the apical surface of kidney epithelia plays a novel and important role in enhancing HIF-1 activity. We have strong preliminary data suggesting that genetic deletion of Muc1 from mouse tubular epithelial cells exacerbates damage especially in the proximal tubule (PT) from IRI, limits adaptive HIF-1 responses, alters tubular metabolism, and inhibits recovery. The central hypothesis of this application is that MUC1 protects the kidney during IRI by transactivation of the HIF-1 adaptive response specifically in the recovering proximal tubule. The specific aims are: 1. To determine if MUC1 protection of the kidney during IRI requires MUC1-dependent HIF-1a nuclear targeting and subsequently transcriptional activation of the HIF-1 pathway specifically in the recovering PT. I will test the hypothesis that MUC1 protects the kidney during IRI by transactivation of the HIF-1 adaptive response in the recovering PT. Experiments are proposed to stabilize HIF-1a in the proximal tubule in the Muc1 KO mice during IRI by introducing a PT KO of VHL, and treatment with vehicle or a specific MUC1 inhibitor to block MUC1 internalization and nuclear delivery. Results of these studies will reveal if MUC1 simply stabilizes HIF-1a levels, or if MUC1 nuclear targeting is essential for transduction of the protective HIF-1 pathway. 2. To characterize the MUC1-HIF-1a complex in cultured kidney cells. I will test the hypothesis that MUC1 stabilizes HIF-1a by direct binding. Experiments are proposed here to characterize the MUC1-HIF-1a complex using both in vitro pull-down assays and co-IP studies in primary PT cells and human kidney cell lines with wild type and mutant constructs, and to determine if MUC1 binding to HIF-1a results in its trafficking to the nucleus. The goal of my research is to fully characterize the MUC1-HIF-1a interaction and determine the mechanism of its protective role in the kidney PT during IRI. This information can be used to design therapies to induce MUC1 and limit the severity of AKI. This award will provide me with additional support to generate preliminary data for an R01-level grant to further investigate whether increased levels of renal MUC1 provide resistance to IRI.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $117,375 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	1/11/2023	NON-COMPETING CONTINUATION	$11,737
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/5/2022	NON-COMPETING CONTINUATION	$105,638
														Subtotal = $117,375

Issue Date FY: 2022 ( Subtotal = $118,158 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/16/2021	NEW	$118,158
														Subtotal = $118,158

Grand Total All Awards = $235,533

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Role of the MUC1/HIF-1a Complex in the kidney proximal tubule during ischemia-reperfusion injury.

Award Number: R03DK131093

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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