# Injury Response Mediated Pathogenesis in Renal Ciliopathies

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2023 · $523,190

## Abstract

PROJECT SUMMARY/ABSTRACT
Primary cilia are present on most renal epithelial cells and their disruption leads to cyst formation. Despite their
clinical importance, the function of the primary renal cilium remains poorly understood. In previous studies, we
and others demonstrated that when cilia assembly (Ift88 mutant) or function (Pkd1 or Pkd2) is disrupted in adult
mice, cysts form slowly in focal areas. This occurs despite nearly all epithelial cells in the kidney being mutant
for these genes. A hint as to why these cysts develop in focal locations in the adult-induced mutants has emerged
from data indicating that renal injury promotes cyst formation and results in cyst formation throughout the kidney.
Based on these data, we propose that PKD2 and cilia regulate renal injury and repair responses and that the
focal cysts in the adult-induced mutants result from a few cells that have experienced an injury. In the absence
of normal cilia function, these cells enter a state of persistent maladaptive repair (as marked by persistent SOX9
expression) and progress to cystogenesis. While cysts are formed in Ift88 and Pkd2 mutants, the cystic kidney
phenotype is always more severe with loss of Pkd2. In double mutants, however, the cystic pathology resembles
the milder Ift88 mutant alone. Our analysis further shows that the inflammatory response following injury in the
Ift88 and Pkd2 mutant mice is altered and as observed with cyst formation; it is exacerbated in Pkd2 mutants
compared to Ift88 or Ift88/Pkd2 double mutants. Collectively, these data suggest that IFT88/cilia and PKD2
regulate signaling activities between the ciliated tubule epithelium and the responding non-ciliated immune cells
for initiation and resolution of an injury response and that cyst formation is promoted when these signaling
pathways are incorrectly controlled. The goals of this proposal are to define the cellular and then molecular
mechanism(s) responsible for the focal and widespread injury-induced cyst formation and how IFT88/cilia and
PKD2 are involved in this process. From this proposal, we will determine whether cilia loss/dysfunction alters the
kidney's sensitivity to injury and results in an increase in the state of epithelial cell maladaptive repair. We will
utilize lineage tracing approaches to determine if descendants of injured cells contribute directly to cyst formation.
We will define new IFT88/cilia and PKD2-dependent intercellular signaling networks involved in the injury and
repair process and how they are dysregulated when cilia are disrupted (Ift88 mutant) or cilia function is perturbed
(Pkd2 mutant). Finally, we will define mechanisms by which loss of Ift88 in a Pkd2 mutant background
suppresses cyst severity through changes in these injury and repair signaling pathways. The data from the
proposal are needed to: 1) elucidate novel functions of the renal cilium, 2) define cellular mechanisms involved
in formation of the sporadic and widespread cysts, 3) understan...

## Key facts

- **NIH application ID:** 10571152
- **Project number:** 2R01DK115752-05A1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Bradley K. Yoder
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $523,190
- **Award type:** 2
- **Project period:** 2023-02-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10571152

## Citation

> US National Institutes of Health, RePORTER application 10571152, Injury Response Mediated Pathogenesis in Renal Ciliopathies (2R01DK115752-05A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10571152. Licensed CC0.

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