Saturday, August 2, 2025 8/2/2025

Role of the COP9 Signalosome (CSN) in kidney disease and hypertension

Award Number: K01DK120790
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 03/02/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2025

Group Awards By:

View Award Description

Role of the COP9 Signalosome (CSN) in kidney disease and hypertension - Project Summary / Abstract Hypertension is the most common risk factor for heart disease and stroke; therefore, it is important to understand the pathogenesis of hypertension for better prevention and treatment. Rare Mendelian causes of hypertension identify previously unrecognized physiological pathways and networks, which can illuminate new treatments for disease. The Mendelian syndrome Familial Hyperkalemic Hypertension (FHHt, or pseudohypoaldosteronism type II) is a monogenic disease resulting from mutations which increase expression of with-no-lysine kinases (WNKs). Cullin-RING ligases (CRLs) were recently discovered to regulate blood pressure via proteasomal degradation of WNKs. Regulation of CRL activity is facilitated by the deneddylase, COP9 Signalosome (CSN), which binds to the complex and removes the ubiquitin-like protein, NEDD8. A mutation in cullin 3 (CUL3) causes FHHt and was shown, by in vitro analysis, to have enhanced CUL3 neddylation, increased degradation of the substrate adaptor kelch-like 3 (KLHL3), and decreased binding to the CSN. We hypothesized that the impaired interaction with the CSN was integral to the disease. The CSN is a well-studied multi-subunit protein, but the data here provides the first evidence that disordered CSN activity in the kidney may relate to hypertension and chronic kidney disease (CKD). The applicant has characterized a genetic mouse model of CSN dysfunction, in which the catalytic subunit of the CSN, Jab1 is deleted from kidney-tubule cells (KS-Jab1-/-). These mice developed an unusual phenotype; there was decreased KLHL3 and upregulation of the WNK-SPAK pathway akin to FHHt, however, several unexpected consequences of Jab1 deletion throughout the nephron were noted that made the observed phenotype differ from the human disease. This included a decrease in the abundance of the Na-Cl co-transporter (NCC) after several weeks, and progressive and spontaneous kidney fibrosis, mimicking chronic kidney disease. Here, the applicant proposes to further explore these provocative results in three specific aims. Aim 1 will continue to test the hypothesis that impaired CSN function causes FHHt by generating mouse models that more faithfully mimic the disease mutation. In Aim 2, a combination of in vitro and in vivo techniques will be used to determine whether the CSN plays a role in modulating NCC directly. Aim 3 will examine the kidney damage caused by deletion of Jab1. Nrf2 accumulation will be investigated as a possible mechanism for the damage by generating Jab1 and Nrf2 double knockout mice. In addition to successful completion of these aims the mentoring and scientific environment make the applicant an ideal candidate to develop independence in renal physiology research. The proposed research will help reveal the mechanisms involved in regulation of blood pressure through the CUL3-KLHL3-WNK4 pathway which could lead to pharmaceutical treatment of hypertension by targeting CRLs, or the CSN. The results will also open two entirely new areas of focus, the role that the CSN plays in regulating NCC degradation and the potential role played by the CSN in mediating or accelerating the development of chronic kidney disease.


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: 2025 ( Subtotal = -$1,403 )
2025	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/24/2025	NON-COMPETING CONTINUATION	-$1,403
														Subtotal = -$1,403

Issue Date FY: 2024 ( Subtotal = $129,719 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/26/2024	NON-COMPETING CONTINUATION	$129,719
														Subtotal = $129,719

Issue Date FY: 2023 ( Subtotal = $129,719 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/23/2023	NON-COMPETING CONTINUATION	$129,719
														Subtotal = $129,719

Issue Date FY: 2022 ( Subtotal = $129,719 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/3/2022	NON-COMPETING CONTINUATION	$129,719
														Subtotal = $129,719

Issue Date FY: 2021 ( Subtotal = $129,719 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/25/2021	NON-COMPETING CONTINUATION	$129,719
														Subtotal = $129,719

Issue Date FY: 2020 ( Subtotal = $131,219 )
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/2/2020	NEW	$131,219
														Subtotal = $131,219

Grand Total All Awards = $648,692

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Role of the COP9 Signalosome (CSN) in kidney disease and hypertension

Award Number: K01DK120790

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 03/02/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer