Transport of organelles and macromolecular complexes through the cytoplasm is essential for every eukaryotic cell. This process is performed by motor proteins that use the energy of ATP hydrolysis to move many types of cargo along microtubules and actin filaments. The spatial and temporal control of motor-dependent transport is critical for cell division, organelle transport and positioning, and the movement of mRNA and protein complexes in the cytoplasm. Defects in organelle transport and motor-associated proteins contribute or cause many neurodegenerative diseases, and mistakes in motor- driven chromosome segregation can cause abnormal development and cancer. The goal of this proposal is to understand how movement of microtubule motors is regulated by accessory proteins and how movement along microtubules generates cell polarity. For analysis of proteins regulating the movement we will use cultured Drosophila S2 cells because they are highly sensitive to protein knock-down by RNAi and movement of cargo along microtubules is not perturbed by other cytoskeletal elements. For analysis of cell polarity we will use primary cultures of Drosophila neurons where microtubules and microtubule motors are key components required for growth of axons and dendrites.
The specific aims of the proposal are: (i) To establish how transport is regulated by local signals (microtubule-binding proteins). (ii) To find contribution of proteins that are not associated with microtubules to transport regulation (iii) To use neuronal model to find how microtubules and microtubule-dependent transport generate formation of cell processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM052111-16
Application #
8732662
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Gindhart, Joseph G
Project Start
1999-07-01
Project End
2015-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60611
Vallotton, Pascal; van Oijen, Antoine M; Whitchurch, Cynthia B et al. (2017) Diatrack particle tracking software: Review of applications and performance evaluation. Traffic 18:840-852
Lu, Wen; Gelfand, Vladimir I (2017) Moonlighting Motors: Kinesin, Dynein, and Cell Polarity. Trends Cell Biol 27:505-514
Barlan, Kari; Gelfand, Vladimir I (2017) Microtubule-Based Transport and the Distribution, Tethering, and Organization of Organelles. Cold Spring Harb Perspect Biol 9:
Steinman, Jonathan B; Santarossa, Cristina C; Miller, Rand M et al. (2017) Chemical structure-guided design of dynapyrazoles, cell-permeable dynein inhibitors with a unique mode of action. Elife 6:
Lu, Wen; Winding, Michael; Lakonishok, Margot et al. (2016) Microtubule-microtubule sliding by kinesin-1 is essential for normal cytoplasmic streaming in Drosophila oocytes. Proc Natl Acad Sci U S A 113:E4995-5004
Lowery, Jason; Jain, Nikhil; Kuczmarski, Edward R et al. (2016) Abnormal intermediate filament organization alters mitochondrial motility in giant axonal neuropathy fibroblasts. Mol Biol Cell 27:608-16
Winding, Michael; Kelliher, Michael T; Lu, Wen et al. (2016) Role of kinesin-1-based microtubule sliding in Drosophila nervous system development. Proc Natl Acad Sci U S A 113:E4985-94
Robert, Amélie; Hookway, Caroline; Gelfand, Vladimir I (2016) Intermediate filament dynamics: What we can see now and why it matters. Bioessays 38:232-43
Engelke, Martin F; Winding, Michael; Yue, Yang et al. (2016) Engineered kinesin motor proteins amenable to small-molecule inhibition. Nat Commun 7:11159
Jolly, Amber L; Luan, Chi-Hao; Dusel, Brendon E et al. (2016) A Genome-wide RNAi Screen for Microtubule Bundle Formation and Lysosome Motility Regulation in Drosophila S2 Cells. Cell Rep 14:611-620

Showing the most recent 10 out of 37 publications