# The Role of Dynein Motor Mutations in Motile Cilia Disease

> **NIH NIH K08** · WASHINGTON UNIVERSITY · 2021 · $159,435

## Abstract

PROJECT SUMMARY
Motile cilia are essential for lung defense, as evidenced by the genetic syndrome primary ciliary dyskinesia
(PCD). PCD is characterized by impaired motile cilia resulting in respiratory distress at birth, followed by chronic
sinopulmonary infection and bronchiectasis, which can lead to respiratory failure. There are no specific therapies
for PCD, in part because key pathways for motile cilia biogenesis and pathogenesis are not defined. PCD has
been linked to mutations in nearly 40 genes. Those that encode dynein proteins, the motors necessary for cilia
beating, comprise the largest class of PCD mutations. We have found that mutations in dynein motor proteins
result in abnormal cytoplasmic aggregates in ciliated cells. Importantly, these aggregates sequester normal
proteins of the machinery required to assemble the dynein motor complexes, suggesting a global disruption of
cilia assembly. To further determine the impact of mutations, we biopsied and cultured airway cells from patients
with PCD, revealing increased expression of genes related to cell stress, including IL-1 and IL6. We hypothesize
that accumulation of mutant protein leads to failure of the cilia assembly machinery and to cellular stress. This
will be tested through the following Specific Aims: (1) Determine how mutant dynein proteins interrupt the
cilia motor assembly pathway and (2) Define the transcriptional and stress responses in cells containing
PCD mutant proteins. We will leverage primary culture nasal cells from patients with mutations in dynein motor
proteins seen at our PCD clinic. To determine how mutant proteins perturb cilia assembly, we will use proteomics
and advanced microscopy to quantify the interaction of the mutant dynein proteins with the assembly machinery.
To characterize the effect of mutant protein on cell stress, we will employ RNA sequencing to define the
transcriptional profile of PCD cells and test known cell stress pathways. Data generated from this proposal will
identify shared pathways in PCD, that can be exploited to develop future therapeutic strategies.
This proposal comprises a plan to provide Dr. Horani with the mentored research, technical skill development,
and tailored didactic training needed to achieve his goal of becoming an independent physician-scientist. The
training will cover areas of genetics and genomics, sequencing data analysis, and advanced fluorescent
microscopy imaging, which are key areas of this proposal. This project will be overseen by a scientific advisory
committee with expertise in motile cilia biology, protein interactions, proteostatic pathways and imaging. The
committee will ensure that career milestones are realized, formal course work is completed, and collaborations
are developed locally and internationally. Findings generated through the proposed studies can be applied to
other genetic airway disease and training will allow Dr. Horani to develop new approaches and therapies that
may improve patient...

## Key facts

- **NIH application ID:** 10098338
- **Project number:** 5K08HL150223-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Amjad Horani
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $159,435
- **Award type:** 5
- **Project period:** 2020-02-10 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10098338

## Citation

> US National Institutes of Health, RePORTER application 10098338, The Role of Dynein Motor Mutations in Motile Cilia Disease (5K08HL150223-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10098338. Licensed CC0.

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