# Biophysical Principles of Microtubule Dynamics

> **NIH NIH R35** · VANDERBILT UNIVERSITY · 2022 · $33,592

## 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 approaches...

## Key facts

- **NIH application ID:** 10630506
- **Project number:** 3R35GM119552-06S1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Marija Zanic
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $33,592
- **Award type:** 3
- **Project period:** 2016-09-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10630506

## Citation

> US National Institutes of Health, RePORTER application 10630506, Biophysical Principles of Microtubule Dynamics (3R35GM119552-06S1). Retrieved via AI Analytics 2026-06-22 from https://api.ai-analytics.org/grant/nih/10630506. Licensed CC0.

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