My long-term goal is to conduct a research program that examines the molecular basis of cellular organization. I have received postdoctoral training in the lab of Dr. John Cooper at Washington University, where I have studied the microtubule motor dynein. All eukaryotes employ microtubule motors such as dynein to organize the intracellular environment in coordination with changes in cell structure and morphology. These scenarios include partitioning the genome during cell division, intracellular transport of proteins and organelles, and perhaps all forms of cell migration. Despite the central role for micortubule motors in these processes, how motors interact with the microtubule substrate in order to produce force is poorly understood. With the research outlined in this proposal, I will develop novel in vivo and in vitro systems to examine how structural features on the microtubule influence motor activity. The development of these tools will be critical for the independent research program that I plan to pursue in my own lab. The broad objective of this proposal is to test the hypothesis that the negatively-charged E-hook motif on the a-tubulin subunit contributes to microtubule function by promoting the binding and/or motility of microtubule motors, and determine whether the role of this motif differs for evolutionarily distinct classes of motors. I will particularly focus on the dynein motor, and seek to identify the molecular basis and consequences of dynein's interaction with the E-hook motif. This project will address these issues by pursuing two aims:
Aim 1. Does the tubulin E-hook promote the activity of microtubule motors in vivo? Aim 2. Direct analysis of dynein motility in the presence of the E-hook mutations. Together these analyses will improve our understanding of microtubule function, and may proove useful for the treatment of human disease. Microtubule motors are involved in many diseases, including neuronal pathologies and tumorigenesis;therefore, understanding the molecular details of motor-microtubule interactions may lead to therapies aimed at altering cellular function by modulating the activity of specific motors.

Public Health Relevance

This project will broaden our understanding of how microtubule motors function, and identify novel pharmacological agents that inhibit dynein activity. This is relevant to human health because he functions of motora are critical to the organization and function of cells. Defects in motor function are known to cause specific diseases, particularly neurological disorders, but the molecular basis of how motor dysfunction contributes to pathology is not understood. Additionally, motors contribute to the progression of other diseases, such as viral infections and tumorigenesis;therefore, understanding the molecular details of motor function will inform strategies for developing effective therapeutics.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Gindhart, Joseph G
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University of Colorado Denver
Schools of Medicine
United States
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Aiken, Jayne; Sept, David; Costanzo, Michael et al. (2014) Genome-wide analysis reveals novel and discrete functions for tubulin carboxy-terminal tails. Curr Biol 24:1295-303
Moore, Jeffrey K (2013) Stopped in its tracks: negative regulation of the dynein motor by the yeast protein She1. Bioessays 35:677-82