Microtubules are critical for nearly every function of eukaryotic cells, from their ability to divide and move to their ability to adopt specific morphologies and withstand mechanical forces. Microtubule assembly, dyamics, and functions are dictated and regulated by a large number of cellular factors including microtubule associated proteins (MAPs) and molecular motors in the kinesin and dynein superfamilies. Our overall goal is to define the mechanisms by which microtubules and kinesin motor proteins drive intracellular trafficking in mammalian cells. To do this, we combine powerful biophysical and biochemical methods that provide mechanistic detail on motor mechanics and motility with cellular assays that report on regulation and function within the complex cellular environment. We will continue to utilize these multi-disciplinary approaches to investigate critical gaps in our knowledge of mechanisms and regulation of intracellular trafficking. We will define mechanisms for targeting of proteins to the primary cilium, a microtubule-based organelle that protrudes from the surface of the cell and drives cell motility and signaling. We will utilize a novel chemical-genetic approach that we developed for engineering inhibitable motors to probe the functions of kinesins critical for the assembly and function of primary cilia. We will determine the motility and force-generating properties of kinesins using both in vitro and cellular assays and use this knowledge to understand how these properties were selected through evolution for specific motor functions in cells. Finally, we will test models of motor regulation by signaling pathways such as Hedgehog ligand. As defects in microtubules and kinesin motors are linked to developmental disorders, neurodegenerative diseases, and cancer, these studies will advance our understanding of their functions in cell biology and disease.

Public Health Relevance

Defects in intracellular transport processes, including mutations in kinesin and dynein motor proteins, are known to contribute to neurodegenerative diseases, cancer, and ciliopathies. This work will utilize biophysical and cell biological approach to reveal basic information about how kinesin motor proteins function within the complex cellular environment. This work will advance our understanding of intracellular trafficking processes and impact our ability to treat human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
1R35GM131744-01
Application #
9698697
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ainsztein, Alexandra M
Project Start
2019-05-01
Project End
2024-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
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