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TWEAK-Fn14 regulation of non-canonical NF-kB signaling in chronic renal inflammation

Award Number: R21DK133754
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/22/2024
PERIOD OF PERFORMANCE END DATE: 08/30/2026

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TWEAK-Fn14 regulation of non-canonical NF-kB signaling in chronic renal inflammation - PROJECT SUMMARY / ABSTRACT An estimated 37 million people in the United States suffer from chronic kidney disease (CKD), which is characterized by steadily declining kidney function due to constitutive inflammation, fibrosis, and tubular atrophy. Current therapeutic approaches are only able to slow CKD progression. Thus, new therapeutic approaches for CKD are urgently required. The NF-κB family of transcription factors is a well-known signaling pathway that is associated with inflammation. However, while canonical NF-κB signaling has been intensely studied, there is compounding evidence that non-canonical NF-κB signaling plays a key role in supporting sustained inflammatory response. Tumor necrosis factor (TNF)-related weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14, also named TNFRSF12a) are among the few identified regulators of non- canonical NF-κB signaling. Studies have shown that TWEAK-induced non-canonical NF-κB signaling is elevated in models of kidney disease and activates proinflammatory cytokines and chemokines in response to acute and sustained kidney injury. Despite the significant progress that has been made in recent years in understanding non-canonical NF-κB signaling, there remains a significant gap in our knowledge of how downstream signaling mechanisms switch to divergent pathways in response to TWEAK stimulation, and less is known about how TWEAK works in synergy with more well-known cytokines such as TNFα and IL-6 in renal cells. The central hypothesis of this proposal is that TWEAK-induced non-canonical NF-κB signaling in renal cells stimulates a unique inflammatory signature when compared to TNFα-driven canonical NF-κB signaling. This proposal seeks to: 1) Identify how TWEAK activates non-canonical NF-κB in renal cells and how these responses are modulated by canonical NF-κB activators; 2) Determine distinct signatures of RelA and p52 transcription factor activity and immune response in cisplatin treated Fn14 knockout mice; and 3) Engineer and validate a cell assay that reports both canonical and non-canonical NF-κB signaling in real time for high-throughput screening (HTS) of TWEAK- FN14 modifiers and inhibitors. The anticipated outcome of this proposal is that we will define key components that differentiate canonical from non-canonical NF-κB signaling, and we will develop a novel screening assay that will be a useful tool in furthering our understanding of chronic inflammation in renal cells. While other studies focus on TNFα and more well-established cytokines, this proposal addresses a significant gap in our knowledge on the interplay between NF-κB signaling pathways and more specifically, how non-canonical NF-κB signaling works in concert to modulate inflammation.


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 = -$710,241 )
2025	2023	THE QUEEN'S MEDICAL CENTER	1301 PUNCHBOWL ST	HONOLULU	HI	96813	HONOLULU	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	1	8/14/2025	TERMINATION	-$632,560
2025	2023	THE QUEEN'S MEDICAL CENTER	1301 PUNCHBOWL ST	HONOLULU	HI	96813	HONOLULU	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	8/1/2025	TERMINATION	$0
2025	2023	THE QUEEN'S MEDICAL CENTER	1301 PUNCHBOWL ST	HONOLULU	HI	96813	HONOLULU	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/30/2025	TERMINATION	$0
2025	2023	UNIVERSITY OF HAWAII	2425 CAMPUS RD SINCLAIR RM 1	HONOLULU	HI	96822	HONOLULU	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	2	8/14/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$556,156
2025	2023	THE QUEEN'S MEDICAL CENTER	1301 PUNCHBOWL ST	HONOLULU	HI	96813	HONOLULU	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	6/20/2025	TERMINATION	-$633,837
														Subtotal = -$710,241

Issue Date FY: 2023 ( Subtotal = $667,500 )
2023	2023	THE QUEEN'S MEDICAL CENTER	1301 PUNCHBOWL ST	HONOLULU	HI	96813	HONOLULU	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	9/7/2023	NEW	$445,000
2023	2023	THE QUEEN'S MEDICAL CENTER	1301 PUNCHBOWL ST	HONOLULU	HI	96813	HONOLULU	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/14/2023	NEW	$222,500
														Subtotal = $667,500

Grand Total All Awards = -$42,741

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TWEAK-Fn14 regulation of non-canonical NF-kB signaling in chronic renal inflammation

Award Number: R21DK133754

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/22/2024

PERIOD OF PERFORMANCE END DATE: 08/30/2026

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