# Regulation of Motile Cilia Assembly in Lung Disease

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $787,475

## Abstract

Project Summary/Abstract
Cilia dysfunction leads to chronic lung disease, as occurs in the genetic syndrome primary ciliary dyskinesis
(PCD) and may contribute to impaired airway clearance in obstructive pulmonary disease (COPD). Unlike
cystic fibrosis, which also causes chronic airway destruction, there is no specific therapy for cilia-related
diseases. We now know that most PCD mutations result in defective production, transport, or proper
placement of ciliary motors along the ciliary axoneme. However, the exact mechanism by which this occurs is
not understood, impeding the development of cilia-specific therapeutic strategies. Thus, our goal is to
determine how ciliary motor components are directed from the cytoplasm, into the cilia, then find their way to
specific sites along the ciliary axoneme. In this proposal, we trace the passage of the multifunctional,
heterodimer CCDC39/CCDC40, which when mutant result in disorganized axonemal microtubule structure and
severe PCD disease. CCDC39 trafficking serves to identify the mechanisms by which ciliary components move
from the cytoplasm, en route to the basal body, and into cilia by intraflagellar transport (IFT). Our preliminary
data indicate that: (1) Ciliary cargoes, including CCDC39, bind centriolar satellite proteins that function as
“cars” to facilitate trafficking to the basal body; (2) CCDC39/CCDC40 are linked to microtubules in association
with two novel “staple” proteins; and (3) CCDC39 is an IFT co-adaptor protein, with ciliary protein MLF1, for
cargo delivery to cilia. We hypothesize that movement of ciliary cargo from the cytoplasm to cilia engages
transport mechanisms using satellite proteins, then co-adapter proteins, including CCDC39/CCDC40, to
properly assemble cilia. We will characterize this series of pathways in the Specific Aims: (1) Determine how
components of motile cilia are trafficked from the cytoplasm to basal bodies; (2) Characterize the
multifunctional protein CCDC39 by biophysical and biochemical means that will identify the role of novel staple
proteins; and (3) Identify the role for CCDC39 and MLF1 as IFT co-adapter proteins in PCD mutants and
COPD tissues. The project uses highly integrated strategies that employ models from single cell organisms to
human tissues carried out by the multidisciplinary Washington University Cilia Group, to define new pathways
for cilia assembly that can be translated to therapies.

## Key facts

- **NIH application ID:** 10376783
- **Project number:** 5R01HL128370-07
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Steven Brody
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $787,475
- **Award type:** 5
- **Project period:** 2015-08-17 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376783

## Citation

> US National Institutes of Health, RePORTER application 10376783, Regulation of Motile Cilia Assembly in Lung Disease (5R01HL128370-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10376783. Licensed CC0.

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