# Role of FBW7 in cystic diseases of the kidney

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2024 · $492,329

## Abstract

Polycystic Kidney Disease is the common denominator in several phenotypically diverse genetic conditions of
the kidney. These diseases include Autosomal Dominant Polycystic Kidney Disease (ADPKD), Autosomal
Recessive Polycystic Kidney Disease, Nephronophthisis (NPHP), and Autosomal Dominant Tubulointerstitial
Kidney Disease (ADTKD). NPHP, which can also be implicated in syndromic forms of PKD such as Joubert,
Bardet-Biedl, and Meckel-Gruber syndrome, together with ADTKD account for 10-20% of children with chronic
renal failure and for 1-5% of all patients undergoing dialysis or transplantation. Mechanisms of cyst development
have been extensively studied using a wide variety of genetic, biochemical, functional, and pharmacological
approaches. While significant progress has been made in identifying the involvement of signaling pathways and
key organelles in disease pathophysiology, the step-by-step mechanisms mediating the architectural and
structural changes of tubular cells during cyst formation and expansion are incompletely understood. It is
becoming increasingly clear that both intrinsic processes such as cell signaling, cell death, and proliferation, as
well as extrinsic factors, such as fibrosis and inflammation influence cystic growth and expansion. Understanding
these processes would be of paramount importance in identifying new, more effective, and specific targets for
pharmacologic intervention. We undertook an approach of proteome reprogramming by deleting the Fbxw7 gene
in tubular cells to identify protein networks responsible for cystogenesis. FBW7 (gene name, Fbxw7) is the
recognition receptor of the SCFFBW7 E3 ligase which processes numerous proteins for ubiquitin-mediated
degradation. Mutant mice developed slowly progressing cystic kidney disease without kidney enlargement,
tubulointerstitial fibrosis, tubular degeneration, and an overall gradual decline in kidney function. These are
cardinal features of NPHP and ADTKD. Aided by the ability to identify direct FBW7 targets, we have identified
protein networks with potential roles in cystogenesis, fibrosis, and tubular degermation. Using this information,
we now aim at understanding how cystogenesis develops, how it is modulated by fibrosis and/or tubular
degeneration, and how these processes impact overall renal function. Successful completion of the proposed
studies will enhance our understanding of cellular mechanisms of cystogenesis, fibrosis, and tubular
degeneration and aid in the identification of new therapeutic targets for PKD.

## Key facts

- **NIH application ID:** 10980662
- **Project number:** 1R01DK138339-01A1
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Leonidas Tsiokas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $492,329
- **Award type:** 1
- **Project period:** 2024-08-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980662

## Citation

> US National Institutes of Health, RePORTER application 10980662, Role of FBW7 in cystic diseases of the kidney (1R01DK138339-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10980662. Licensed CC0.

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