# Molecular dissection of the ciliary gate

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2024 · $417,623

## Abstract

Project Summary
Primary cilia are microtubule-based sensory structures found on the surface of most eukaryotic cells.
Dysfunctional cilia lead to numerous syndromic disorders, often characterized by renal abnormalities. Unlike
other cellular organelles, the ciliary lumen is open to the cytoplasm, making it unclear how cilia-essential and
renal-physiology-related proteins, such as Polycystin 1 and 2 from ADPKD, reach the cilia. There is growing
evidence to support the existence of a selective gate at cilia base that regulates the import of ciliogenic
proteins. Despite the poorly studied transition fibers (TFs) being implied to be a vital part of the ciliary gate,
there is a lack of molecular insight into the establishment of TFs, either in terms of their structure or function.
 Investigating the connection between cilia and disease in mammalian models can be challenging due to
the essential roles of cilia in mammalian embryonic development. Thus, alternative experimental systems are
needed. Caenorhabditis elegans has proven to be an effective model for studying ciliary proteins in their
natural cellular environment due to its highly conserved cilia composition and signaling. Our laboratory
pioneered the application of C. elegans to study the ciliary gate in past funding periods and made important
discoveries about its composition, establishment, and significance in human diseases. Our recent findings
have shown that the ARPKD protein DZIP1L plays a crucial role in establishing functional cilia gates in both C.
elegans and human renal epithelial cilia. Building on our expertise in cilia research and utilizing the resources
of the Mayo Clinic PKD Translational Center, our main objective is to fundamentally advance the
understanding of the physiological importance of cilia gating in ciliopathies beyond Polycystic Kidney
Disease. This proposal is based on a novel discovery that DZIP1L and ANKRD26 forms a conserved protein
module to recruit other essential TF proteins to build a functional cilia gate; a paradigm that the activity of a
poorly defined phosphoinositide signaling, mediated by the ciliary PIPKg, determines the proper localization of
DZIP1L; and an exciting hypothesis that the ARPKD variants of DZIP1L may specifically impact cilia import of
polycystins. Emerging evidence from our laboratory and others shows that polycystin dosage closely correlate
with the severity of various PKD conditions, highlighting the therapeutic potential of targeting cilia gating to
enhance the import of PKD proteins. To comprehensively understand the regulatory pathways of DZIP1L-
regulated cilia gating, especially for PKD proteins, we will use both C. elegans and mammalian renal cell
models and employ an interdisciplinary approach. Our goal is to gain critical insights into this understudied
area in cilia and ciliopathies, establish its physiological significance, and link fundamental discoveries to the
molecular connections between aberrant cilia gating and the d...

## Key facts

- **NIH application ID:** 10801027
- **Project number:** 2R01DK099160-10
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Jinghua Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $417,623
- **Award type:** 2
- **Project period:** 2014-08-15 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801027

## Citation

> US National Institutes of Health, RePORTER application 10801027, Molecular dissection of the ciliary gate (2R01DK099160-10). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10801027. Licensed CC0.

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