# Structure and mechanism of the centrosome-cilium complex

> **NIH NIH R35** · STANFORD UNIVERSITY · 2023 · $648,523

## Abstract

Abstract
The centrosome-cilium complex is a critical organelle of animal cell function. The centrosome is
the main microtubule organizing center of animal cells, and the centrioles within the centrosome
have a unique structure that allows them to serve as initiators of the assembly of a cilium.
Primary cilia are small, antenna-like organelles critical for vertebrate development and
physiology. Defects in the centrosome-cilium complex result in human diseases called
ciliopathies, characterized by a wide spectrum of phenotypes, highlighting their important role in
multiple cell types and organs. This complex forms a distinct compartment of the cell, with a
highly polarized microtubule cytoskeleton directing intracellular traffic to and from it, and a
specialized segment of the plasma membrane surrounding part of it. In most cells, there is only
one centrosome-cilium complex, but this is often altered in cells from a range of diseases, and
in cells that have specific developmental programs to amplify centrioles. The function of cilia
critically depends on the dynamic changes in protein composition and localization. In particular,
Hedgehog (Hh) signaling transduction, essential for embryonic development, adult tissue
regeneration and cancer, largely takes place at primary cilia, and involves movements of the
signaling proteins into and out of the cilium in response to signal. We have defined six
fundamental questions that drive the proposed research.
1) How do the specialized compound microtubules of centriole form, and how do they
specifically form only at the centriole?
2) How are centrioles functionalized to carry out the essential roles of cilium formation,
centrosome formation, duplication?
3) What are the consequences of failure to maintain centriole number, and what homeostatic
mechanisms exist that could facilitate a return to the normal state?
4) What mechanisms promote centriole amplification and loss in specific differentiated contexts?
5) What is the behavior of signaling proteins in the cilium, at the single molecule level, and how
does it change in response to activation of the pathway?
6) How are cilia disassembled and is the same mechanism used in different contexts and
across evolution?
We will use a combination of advanced imaging, cell culture and in vitro differentiation models,
combined with sophisticated molecular biology to address these questions. Successful
outcomes in these experiments will inform our understanding of centrosome-cilium defects in
disease states, including ciliopathies and cancer, and potentially lead to new therapeutic
approaches.
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## Key facts

- **NIH application ID:** 10594530
- **Project number:** 5R35GM130286-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Tim Stearns
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $648,523
- **Award type:** 5
- **Project period:** 2019-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10594530

## Citation

> US National Institutes of Health, RePORTER application 10594530, Structure and mechanism of the centrosome-cilium complex (5R35GM130286-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10594530. Licensed CC0.

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