# Ciliary Disassembly, a modifier of Autosomal Dominant Polycystic Kidney Disease

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2024 · $342,055

## Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common genetic diseases affecting
12.5 million people worldwide and by far, the most common genetic disease of the kidney. It is caused by
inactivating mutations in the PKD1 or PKD2 genes, encoding a receptor-channel complex (Polycystins or
PKD1/PKD2). A hallmark of ADPKD is increased cell proliferation. However, how mutations in the Polycystin
genes cause increased cell proliferation is not completely understood. A key organelle in disease development
and progression is the primary cilium, an antenna-like organelle housing several mitogenic signaling pathways.
Genetic and pharmacologic studies show that primary cilia ablation or acceleration of cilia disassembly reduces
cell proliferation, suppresses cystic growth and improves kidney function, whereas deceleration of ciliary
disassembly has the opposite effects in mouse models of ADPKD. While these observations are of paramount
importance in understanding the pathophysiology of ADPKD and in developing therapeutic approaches to slow
down disease progression, a unifying theory connecting cilia and cell proliferation in ADPKD is lacking. Ciliary
assembly and disassembly or shedding are normal processes of actively proliferating cells. Cilia assemble in
quiescent cells, while disassemble or shed when cells re-enter the cell cycle (G1/S). Our preliminary data show
that deletion of Pkd1 increases the activity/levels of p53, which in turn, induces the expression of the substrate
recognition receptor FBW7 of the SCFFBW7 Ubiquitin E3 ligase. FBW7 targets for proteasomal degradation a
subset of disassembly factors delaying deciliation and stabilizing primary cilia. Continuous presence of cilia
during the G1/S transition leads to sustained mitogenic signaling mediated by stabilized/remaining cilia resulting
in more cells eventually entering the cell cycle. Finally, genetic modifications of this pathway, improve renal
function of Pkd1-null mice. These results help explain the increased cell proliferation seen in ADPKD kidneys
and the positive effect of cilia on disease progression. Using a vertical approach combining biochemical, cell
biological, and genetic methods, we will determine the role of ciliary disassembly and shedding in cystic kidney
disease progression. Successful completion of the proposed will have a significant impact on our understanding
the biological role of ciliary disassembly/shedding in disease progression and on helping develop new
therapeutic approaches for ADPKD.

## Key facts

- **NIH application ID:** 10765648
- **Project number:** 5R01DK126705-04
- **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:** $342,055
- **Award type:** 5
- **Project period:** 2021-03-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765648

## Citation

> US National Institutes of Health, RePORTER application 10765648, Ciliary Disassembly, a modifier of Autosomal Dominant Polycystic Kidney Disease (5R01DK126705-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10765648. Licensed CC0.

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