# Molecular Mechanisms of Axonal Transport and Organelle Dynamics

> **NIH NIH R35** · UNIVERSITY OF PENNSYLVANIA · 2020 · $662,798

## Abstract

Project Summary
Molecular motors drive the active transport of organelles along the cellular cytoskeleton. This transport is
critically important in neurons, highly polarized cells that extend axons up to 1m. Axons are continuously
supplied with newly synthesized proteins and organelles from the cell body; active clearance of aging proteins
and dysfunctional organelles is also required to maintain axonal homeostasis. Thus, axonal transport driven by
the coordinated activities of cytoplasmic dynein and kinesin motors is essential, and deficits in this transport
cause neurodegeneration. Here we focus on the molecular coordination of dynein and kinesin motors during
axonal transport by scaffolding proteins and effectors, and the upstream regulatory kinases and phosphatases
that maintain a sustained regulatory state over long length- and time-scales. We are also interested in
interactions between microtubule- and actin-based motors, which affect both the initiation and termination of
motility. Finally, we are interested in the mechanisms by which molecular motors and cytoskeletal dynamics
actively remodel organelle membranes, leading to deformation, tubulation, fission and fusion. We will tackle
these questions using the synergistic approaches of live cell imaging and in vitro reconstitution with single
molecule resolution to understand the mechanisms involved. We will focus on three major goals. Goal 1:
Understanding the integrated regulation of organelle transport. Each type of organelle moving along the
axon has a distinct pattern of motility that directly relates to its function, but we do not yet fully understand the
mechanisms regulating this transport. We will focus on essential axonal cargos, autophagosomes and
signaling endosomes, testing the model that the cargo-specific, integrated regulation of motors allows for
sustained transport over long time scales and distances. In Goal 2, we seek to understand the localized
regulation of organelle dynamics within defined axonal zones, including the axon initial segment,
presynaptic sites, and the axon terminal. These zones exhibit distinct trafficking patterns that correspond to
differences in cytoskeletal organization: microtubule bundling, plus-end dynamics, post-translation
modifications of tubulin, and intersections with actin filaments. We are interested in mechanisms that enhance
the rate-limiting step of transport initiation, mediate compartment-specific sorting, and control cargo
delivery/retention at specific sites of cellular need. And in Goal 3, we will study organelle remodeling driven
by opposing motors and/or cytoskeletal dynamics. While some organelles move through the cell with little
evident change in morphology, other cargos are dramatically remodeled, undergoing tubulation, fission or
fusion. We hypothesize that molecular motors and cytoskeletal filaments provide an adaptable toolbox that can
be specifically tuned to regulate dynamic organelle morphology. Together, these approach...

## Key facts

- **NIH application ID:** 9922337
- **Project number:** 5R35GM126950-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Erika L Holzbaur
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $662,798
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922337

## Citation

> US National Institutes of Health, RePORTER application 9922337, Molecular Mechanisms of Axonal Transport and Organelle Dynamics (5R35GM126950-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9922337. Licensed CC0.

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