Molecular motors that drive cargo transport along cytoskeletal filaments are critical for processes such as cell division, cell motility, intracellular trafficking and ciliary function. Kinesins are a superfamily of molecular motors that use the energy of ATP hydrolysis to move along or destabilize microtubule filaments. Much attention has been paid to the chemomechanical cycle and cellular functions of kinesin motors. An important aspect that is less understood is how motor proteins are regulated in cells to ensure their activity at the proper place and time. By using in vivo model systems that incorporate the complexity of cargo/motor complexes and their regulatory mechanisms, as well as in vitro biochemical and biophysical methods, we aim to understand the regulatory mechanisms that control kinesin activity and transport events inside cells. We will analyze roles of different kinesin-2 family members in intraflagellar transport (IFT) and specifically, their contributions to building primary cilia versus the delivery of molecules required for sensation and signaling. We will determine the mechanisms by which ciliary access of kinesin motors is regulated by importin proteins and a Ran gradient. We will explore the regulatory mechanisms that control kinesin motor activity and location during ciliary resorption and entry into mitosis. This work will provide exciting new insights into how the regulation of motor proteins gives rise to coordinated transport of protein complexes in cells and will suggest therapeutic targets in human disease.

Public Health Relevance

Kinesin motors are nanomachines that drive cellular processes such as cell division, intracellular transport, and ciliary function. The work in this proposal will aid in the knowledge and treatment of kinesin-based human pathologies such as neurodegeneration, cancer and a group of diseases known collectively as the ciliopathies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM070862-09
Application #
8608538
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Gindhart, Joseph G
Project Start
2005-07-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
9
Fiscal Year
2014
Total Cost
$295,620
Indirect Cost
$97,620
Name
University of Michigan Ann Arbor
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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