# Control of cargo distributions by microtubule motor physical interactions with cargo, cytoplasm and MAPs

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $347,625

## Abstract

PROJECT SUMMARY
The major open question in microtubule motor research is to determine how cargo-scale
motor behavior is regulated (at the molecular scale) to orchestrate control of a cell's
spatial organization (on the scale of 10-100 microns), simultaneously for all of motor-
driven intracellular traffic. This involves the microtubule associated protein Tau, the
hallmark of Tauopathy diseases. Challenges arise because of the combinatorial
complexity of Tau variants and the multi-scale nature of the question – two challenges
for which computational modeling is particularly well suited to confront. In Aim 1, we will
develop a model to simulate motor-MAP kinetics and how these lead to cargo transport.
We hypothesize that a microtubule adorned with MAPs and other molecules can
selectively influence cargo localization depending on the cargo's size and mechanical
deformability. This selectivity can be understood in terms of the MAP's size, mechanical
properties and abundance, which together provide a traffic coding system that is mis-
regulated in disease. We will develop a computational model and simulate motor
transport at the cargo-scale to explore specificity and multiplexing by MT-cargo spacing
control. A key missing parameter is the motor's attachment rates, which have been so
far too technically challenging to measure directly and will therefore require a novel
experimental-theoretical assay. We will then simulate motor transport in a 1-dimensional
array of microtubules to identify cargo-scale parameters that sensitively lead to cell-scale
localization, using known spatial heterogeneity of, e.g., Tau across axons. In Aim 2, we
will explore the spacing-based aspect of motor modulators. We hypothesize that many
transport-regulating molecules operate in part by tuning the spacing (mean and variance
of distance) between the microtubule and cargo. Spacing-based regulation endows the
system with control properties not present in other modes of regulation. We will develop
an optical tweezer-based assay to quantify the modulation of transport parameters by
tuning MT-cargo spacing, and a simulation-based inference method to measure spacing
for arbitrary MAPs. We will specifically work to understand the regulatory mechanism of
highly-structured molecules such as Dynactin and Rabs, and highly-disordered
molecules such as Tau and MAP2. In Aim 3, we will explore the effects of the cargo's
and cell's local rheology. We hypothesize that both the internal dynamics of surface-
bound molecules on the cargo, and the cell's local rheology influence transport
properties. This provides the system with a natural cargo sorting mechanism. Using our
simulation, we will quantify the influence of the cargo's internal viscosity (low for
vesicular cargo, intermediate for lipid droplets, and high for rigid cargo like RNA) and
how this interacts with the viscoelasticity of the cytoplasm.

## Key facts

- **NIH application ID:** 9903391
- **Project number:** 5R01GM123068-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Jun Allard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,625
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903391

## Citation

> US National Institutes of Health, RePORTER application 9903391, Control of cargo distributions by microtubule motor physical interactions with cargo, cytoplasm and MAPs (5R01GM123068-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9903391. Licensed CC0.

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