# Structural basis of dynein-driven ciliary motility

> **NIH NIH R35** · YALE UNIVERSITY · 2022 · $250,000

## Abstract

Research Strategy:
Summary:
Cilia and flagella are evolutionarily conserved appendage-like organelles that sense the extracellular
environment, drive the movement of individual cells, or transport fluids. Defects of ciliary functions lead to
numerous diseases termed the ciliopathies, which result in a variety of congenital disorders and cause a broad
spectrum of symptoms. The outer-arm dynein (OAD) is a key motor protein that generates most mechanical
forces to power the ciliary beating by ATP hydrolysis. OAD mutations were found in over half of the primary
ciliary dyskinesia (PCD) patients. These mutations have orthologs in algae and ciliates, which also lead to
cilia/flagellar dysfunctions, suggesting that the lower species and humans have important commonalities on the
mechanisms of ciliary motility. However, lacking an atomic model of most ciliary components has been a main
barrier to our understanding the cilium system. We will use the model systems T. thermophila and C. reinhardtii
to elucidate the cilium assembly and dynein-driven ciliary motility in the following years, with an emphasis on
OAD and its regulation. We aim to reveal the mechanisms in atomic details by a combination of cryo-EM/ET,
correlative light and electron microscopy (CLEM), biochemistry, cell biology, single-molecule biophysics, and
computational modeling etc. Our aims for the following years are to understand how OAD arrays are formed in
cilia, how OADs coordinate with each other during beating, how the OAD activity is regulated by other ciliary
components (such as central pair) and extracellular signals, and build an atomic model of axoneme. We will
co-develop cryo-EM/ET methods to address long-standing problems. The revealed mechanisms will provide
more accurate information for our future mutagenesis in mammalian systems and human disease models.

## Key facts

- **NIH application ID:** 10582036
- **Project number:** 3R35GM142959-02S1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Kai Jack Zhang
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $250,000
- **Award type:** 3
- **Project period:** 2021-09-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10582036

## Citation

> US National Institutes of Health, RePORTER application 10582036, Structural basis of dynein-driven ciliary motility (3R35GM142959-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10582036. Licensed CC0.

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