# Biophysical Principles of Microtubule Dynamics

> **NIH NIH R35** · VANDERBILT UNIVERSITY · 2022 · $416,063

## Abstract

PROJECT SUMMARY
Dynamic remodeling of the microtubule cytoskeleton is crucial for a variety of cellular processes, including cell division, cell
motility and differentiation. Microtubule cytoskeleton reorganization relies on the control of individual microtubule polymers,
which switch between phases of growth and shrinkage through a process known as microtubule dynamic instability.
Although dynamic instability was discovered decades ago, the molecular mechanisms that underlie microtubule catastrophe
and rescue, the transitions between phases of growth and shrinkage, and their control through collective effects of a myriad
of regulators are still being unraveled. The goal of this project is to elucidate the fundamental mechanisms underlying
microtubule dynamics. Our central hypothesis is that conditions experienced at the time of growth have long-term effects
on subsequent microtubule behavior, including catastrophe, shrinkage and rescue. To test this hypothesis, we will employ
highly-controlled in vitro reconstitution experiments, combining purified protein components, microfluidics and high
spatiotemporal resolution light-microscopy approaches. We will determine the different impacts of distinct growth conditions
at the two microtubule ends, giving rise to their unique dynamic behaviors. We will elucidate individual and combined effects
of microtubule regulators and their underlying mechanisms. We will particularly focus on microtubule regulators that bind
both soluble and polymeric form of tubulin. At the plus end, we will investigate TOG-domain proteins XMAP215 and CLASP
to elucidate the similarities and differences in their mechanisms underlying their differential effects on plus-end dynamics.
At the minus end, we will investigate the interplay of stabilizing regulators, including Kinesin-14 HSET, and destabilizing
regulators, including tubulin-sequestering protein Op18/Stathmin and a poorly-studied microtubule severing protein
Fidgetin. Since every one of these microtubule regulators has been implicated in human disease, particularly cancer and
neurodevelopmental disorders, revealing their mechanisms of action is of direct health relevance. Our quantitative in vitro
measurements will enable us to develop mathematical and computational models reconciling the dynamics of both
microtubule ends, and encompassing the collective effects of regulators at each end. We will directly test the models
developed based on our in vitro and in silico findings in physiologically-relevant contexts using state-of-the-art fast super-
resolution quantitative live cell imaging. Beyond uncovering the fundamental mechanisms underlying microtubule dynamics
in cells, we will expand our cellular studies with a focus on the role of CLASP in cell migration and neuronal development.
Our cellular investigations will invariably yield new hypotheses to be tested by controlled in vitro and in silico experiments.
The continuous feedback between in vitro and cellular approache...

## Key facts

- **NIH application ID:** 10330644
- **Project number:** 2R35GM119552-06
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Marija Zanic
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $416,063
- **Award type:** 2
- **Project period:** 2016-09-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10330644

## Citation

> US National Institutes of Health, RePORTER application 10330644, Biophysical Principles of Microtubule Dynamics (2R35GM119552-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10330644. Licensed CC0.

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