# Structure and Function of Complexes that Regulate Ciliary Motility

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $511,672

## Abstract

PROJECT SUMMARY
The overall goal of the proposed research is to provide a better understanding of how cilia move by dissecting
the structure and function of ciliary complexes that regulate dynein activity and ciliary motility. Cilia and flagella
are conserved and ubiquitous microtubule-based organelles with important roles in cell locomotion, fluid
transport, sensation, cell signaling, and development, which are critical processes for the survival and proper
function of many eukaryotic cells and tissues. In humans, defects in the motility and assembly of cilia are
responsible for numerous congenital diseases, such as primary ciliary dyskinesia, chronic respiratory disease,
infertility, brain developmental defects, congenital heart disease, and randomization of the left-right body axis.
Our previous studies of both inhibited and actively beating wild type and mutant cilia have opened a new window
into the functional organization of motile cilia. However, long-standing fundamental questions remain, for
example, about how regulatory signals change dynein’s activity on a molecular level, what are the roles of the
different regulatory complexes during ciliary motility, and how dyneins are spatially and temporally coordinated
to generate the oscillatory beating typical for cilia. Building on a strong premise of both published and preliminary
data, this proposal directly addresses these critical open questions through three specific aims that are directed
at (Aim 1) revealing the proteome and near-atomic resolution structure of the full-length radial spoke RS3 in
mouse respiratory cilia, (Aim 2) understanding the functional roles of the regulatory ATPase domain of DRC11
– a nexin-dynein regulatory complex subunit – for proper regulation of ciliary motility, and (Aim 3) characterizing
ciliary components that assemble only on specific doublets to ascertain if their inherently asymmetric distribution
contributes to generating ciliary beating and/or different waveforms. We use a powerful and innovative
combination of modern approaches, including a multi-scale imaging approach that combines near-atomic
resolution cryo-EM single particle analysis, cryo-electron tomography to image mutant cilia and tagged proteins
with molecular resolution, and expansion light microscopy to determine the doublet-specific distribution of
specific ciliary proteins. We expect that our combined studies will provide important new conceptual and
mechanistic insights into ciliary motility and regulation, which will also impact our understanding of ciliary
diseases.

## Key facts

- **NIH application ID:** 10891240
- **Project number:** 2R01GM083122-14
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Daniela Nicastro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $511,672
- **Award type:** 2
- **Project period:** 2007-09-28 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891240

## Citation

> US National Institutes of Health, RePORTER application 10891240, Structure and Function of Complexes that Regulate Ciliary Motility (2R01GM083122-14). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10891240. Licensed CC0.

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