The microtubule cytoskeleton provides a structural framework for the transport and positioning of membrane organelles and macromolecules, and is essential for cell division, cell motility and cell signaling. Disruption of microtubule-dependent transport underlies the pathogenesis and progression of cancer and neurodegeneration. Understanding the molecular mechanisms that control MT-dependent motility and MT organization is of paramount significance for the development of MT-based therapeutic interventions, many of which are being clinically applied. Recently, we discovered that a novel family of GTPases termed septins is essential for the microtubule-dependent transport of chromosomes and membrane vesicles. Septins are linked to a diversity of cancers and neurodegenerative diseases including Alzheimer's and Parkinson's. The long-term goal of our research is to understand how septins function in microtubule-dependent motility. We hypothesize that septins selectively modulate the interaction of microtubules with motors and microtubule-associated proteins (MAPs). Here, we will determine the molecular mechanism by which septins interact with microtubules. Importantly, we will test how septins influence the microtubule binding of specific motors and MAPs. We will use this knowledge to elucidate septin roles in the directionality and/or velocity of membrane traffic in live epithelia and neurons. Because the directionality of intracellular transport is influenced by the stability and orientation of individual microtubule tracks, we will examine how septins control the spatial organization and stability of microtubules. Our studies will provide new insights into the regulation of microtubule-dependent transport, and generate a model for the design of septin-based therapeutics (e.g., inhibitory peptides), which can be used as an alternative to microtubule-targeting agents.

Public Health Relevance

We have identified a new family of proteins, which regulate the movement of membranous organelles and chromosomes in cells. Because these molecules are abnormally expressed in neurodegenerative diseases and cancer, we are interested in understanding: 1) how they work, 2) how they contribute to disease, and 3) how we can manipulate them to design new therapies against cancer and neurodegenerative diseases such as Alzheimer's and Parkinson's.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM097664-04
Application #
8705280
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Gindhart, Joseph G
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Drexel University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Mostowy, Serge; Bi, Erfei; Fuchtbauer, Ernst-Martin et al. (2014) Highlight: the 5th International Workshop on Septin Biology. Biol Chem 395:119-21
Angelis, Dimitrios; Karasmanis, Eva Pauline; Bai, Xiaobo et al. (2014) In silico docking of forchlorfenuron (FCF) to septins suggests that FCF interferes with GTP binding. PLoS One 9:e96390
Dolat, Lee; Hunyara, John L; Bowen, Jonathan R et al. (2014) Septins promote stress fiber-mediated maturation of focal adhesions and renal epithelial motility. J Cell Biol 207:225-35
Cui, Cheng; Chatterjee, Bishwanath; Lozito, Thomas P et al. (2013) Wdpcp, a PCP protein required for ciliogenesis, regulates directional cell migration and cell polarity by direct modulation of the actin cytoskeleton. PLoS Biol 11:e1001720
Spiliotis, Elias T; Gladfelter, Amy S (2012) Spatial guidance of cell asymmetry: septin GTPases show the way. Traffic 13:195-203