Project Grant R21DK133754

TWEAK-FN14 REGULATION OF NON-CANONICAL NF-KB SIGNALING IN CHRONIC RENAL INFLAMMATION - 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- ASSOCIATED WITH INFLAMMATION. HOWEVER, WHILE CANONICAL NF- COMPOUNDING EVIDENCE THAT NON-CANONICAL NF- RESPONSE KB FAMILY OF TRANSCRIPTION FACTORS IS A WELL-KNOWN SIGNALING PATHWAY THAT IS KB SIGNALING HAS BEEN INTENSELY STUDIED, THERE IS KB SIGNALING PLAYS A KEY ROLE IN SUPPORTING SUSTAINED INFLAMMATORY . 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- KB SIGNALING. STUDIES HAVE SHOWN THAT TWEAK-INDUCED NON-CANONICAL NF- KB 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- KB 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 TNF HYPOTHESIS OF THIS PROPOSAL IS THAT TWEAK-INDUCED NON-CANONICAL NF- UNIQUE INFLAMMATORY SIGNATURE WHEN COMPARED TO TNF TO: 1) IDENTIFY HOW TWEAK ACTIVATES NON-CANONICAL NF- BY CANONICAL NF- A AND IL-6 IN RENAL CELLS. THE CENTRAL KB SIGNALING IN RENAL CELLS STIMULATES A A-DRIVEN CANONICAL NF- KB SIGNALING. THIS PROPOSAL SEEKS KB IN RENAL CELLS KB ACTIVATORS; 2) DETERMINE DISTINCT SIGNATURES OF RELA AND P52 TRANSCRIPTION FACTOR ACTIVITY AND AND HOW THESE RESPONSES ARE MODULATED IMMUNE RESPONSE IN CISPLATIN TREATED FN14 KNOCKOUT MICE; AND 3) ENGINEER AND VALIDATE A CELL ASSAY THAT REPORTS BOTH CANONICAL AND NON-CANONICAL NF- KB 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- KB 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 TNF A AND MORE WELL-ESTABLISHED CYTOKINES, THIS PROPOSAL ADDRESSES A SIGNIFICANT GAP IN OUR KNOWLEDGE ON THE INTERPLAY BETWEEN NF- KB SIGNALING PATHWAYS AND MORE SPECIFICALLY, HOW NON-CANONICAL NF- KB SIGNALING WORKS IN CONCERT TO MODULATE INFLAMMATION.