# Molecular Mechanisms of Axonal Transport and Organelle Dynamics

> **NIH NIH R35** · UNIVERSITY OF PENNSYLVANIA · 2024 · $704,950

## Abstract

Molecular motors drive the active transport of organelles along the cellular cytoskeleton. Organelle transport
is critically important in neurons, cells that extend axons reaching up to 1m in length. Axons have limited
capacity for biosynthesis and degradation, thus axonal transport is required to supply newly synthesized
proteins and organelles and to remove aging proteins and dysfunctional organelles. Accumulating evidence
supports a cargo-specific model for axonal transport, in which the opposing activities of kinesin and
cytoplasmic dynein motors are regulated by a distinct complement of regulatory proteins including scaffolding
proteins and activating adaptors. We are interested in the mechanisms that regulate the transport of key
organelles including mitochondria, autophagosomes, and synaptic vesicle precursors. We are also interested
in the mechanisms that lead to site-specific delivery, such as the targeting of newly synthesized synaptic
components to presynaptic sites along the axon. We hypothesize that this delivery is dependent on the
localized regulation of cytoskeletal dynamics and organization, which directly affect the initiation and
termination of cargo motility. Finally, we are interested in the mechanisms by which molecular motors and
cytoskeletal dynamics actively remodel organelle membranes, leading to tubulation, fission and fusion. We
tackle these questions using the synergistic approaches of live cell imaging and in vitro reconstitution with
single molecule resolution. We will continue to focus on three major goals. Goal 1: Understanding the
integrated regulation of organelle transport. Each type of organelle transported along the axon has a
distinct pattern of motility that directly relates to its function. We seek to understand the specific mechanisms
involved, focusing on essential axonal cargos, such as mitochondria and autophagosomes, 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, such as the delivery of synaptic vesicle precursors to presynaptic sites along the
axon. These zones exhibit distinct patterns of cytoskeletal organization and cytoskeletal dynamics. We are
interested in the mechanisms that enhance the rate-limiting step of transport initiation and control cargo
delivery/retention at specific sites of cellular need. And in Goal 3, we will study organelle remodeling driven
by molecular motors and/or cytoskeletal dynamics. Organelles such as mitochondria undergo dramatic
remodeling via mechanisms including fission and 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 approaches will provide important new insights into organelle
dynamics in neurons. As deficits in axonal tr...

## Key facts

- **NIH application ID:** 10831462
- **Project number:** 5R35GM126950-07
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Erika L Holzbaur
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $704,950
- **Award type:** 5
- **Project period:** 2018-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831462

## Citation

> US National Institutes of Health, RePORTER application 10831462, Molecular Mechanisms of Axonal Transport and Organelle Dynamics (5R35GM126950-07). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10831462. Licensed CC0.

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