# Molecular modulators of polycystin signaling

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $423,958

## Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease that results from
mutations in either of two proteins, polcysytin-1 (PC1) or polycystin-2 (PC2). More than two decades have passed
since the genes encoding these proteins were discovered and there has been significant progress in
understanding the functions of polycystins and their associated disease. Nonetheless, there remain substantial
gaps in knowledge and lack of consensus about the precise functions of PC1 or PC2 and the mechanisms of
ADPKD. Resolution of these gaps is of great significance given our expectation that optimal therapies for ADPKD
are best developed based on the fundamental understanding of polycystin function in the mammalian kidney.
Much of the current mechanistic understanding of polycystin function is based on studies of candidate pathways
drawn from amongst known cellular mechanisms associated with functions such as differentiation, proliferation,
transport and signaling. The lack of coalescence toward an interrelated unifying functional pathway in polycystin
biology and the persistence of gaps in understanding of in vivo polycystin function despite extensive investigation
suggests that the critical components of the most proximal polycystin signaling cascade have yet to be identified.
Indeed, the polycystins were discovered as complex, entirely novel proteins and it stands to reason that they
may function in a signaling pathway that is not among those that are currently well understood or studied. We
made use of this concept in by applying an unbiased in vivo transcriptomic study using Translating Ribosome
Affinity Purification (TRAP) RNASeq. From this, we identified upregulation of cell cycle and down regulation of
oxidative phosphorylation as key pathways alterations in vivo. Among these, we found genotype dependent
upregulation of a cilia associated transcription factor, Glis2, not previously considered to function in polycystin
signaling or ADPKD pathogenesis. We made double mutants of Pkd1 with Glis2 in early onset and adult models
and found Glis2 dosage-dependent rescue of cyst formation in both. Based on these findings we propose that
Glis2 is a candidate for a downstream effector of PC1 function that is critical for cyst progression in ADPKD. In
this study, we will determine the in vivo mechanism of action of Glis2 and establish its effects on cyst cell
proliferation, apoptosis and ADPKD due to Pkd2. We will determine whether Glis2 is a target for therapy through
both genetic and pharmacotherapeutic studies. We will assess whether in vivo genotype dependent
transcriptional changes we have identified are similarly extended to cell culture systems with Pkd mutant
genotypes. We will also evaluate the functional properties of Glis2 protein in Pkd mutant cell lines. In aggregate,
these studies open a new direction of investigation for polycystin signaling and ADPKD pathogenesis.

## Key facts

- **NIH application ID:** 10356036
- **Project number:** 5R01DK120911-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** STEFAN SOMLO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,958
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10356036

## Citation

> US National Institutes of Health, RePORTER application 10356036, Molecular modulators of polycystin signaling (5R01DK120911-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10356036. Licensed CC0.

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