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Towards deciphering the tubulin code: Identifying the contribution glutamylation makes to regulation of microtubule dynamics

Award Number: R15GM135886
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/17/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2023

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Towards deciphering the tubulin code: Identifying the contribution glutamylation makes to regulation of microtubule dynamics - PROJECT SUMMARY A major deficit in our understanding of microtubule function is a lack of knowledge of how tubulin post translational modifications such as glutamylation impact microtubule dynamics. Altered glutamylation is associated with human ciliopathies and neurodegeneration therefore there is a critical need to identify the specific contributions glutamylation makes to modulating microtubule properties. Studies that have focused on individual glutamylating or deglutamylating enzymes have revealed functions for glutamylation in the maintenance of cilia stability and intracellular transport, but the effect on the microtubule dynamics remains obscure. The overall objective of the proposed study, is to determine the contribution tubulin glutamylation makes to regulating microtubule properties and the stability of the microtubule-based centriole. Preliminary findings show that glutamylation aids tolerance of cold and colchicine, stressors that destabilize the microtubules. The central hypothesis guiding the proposed work is that tubulin glutamylation modulates microtubule dynamics to tailor microtubule stability to cellular needs, including tolerance of stressors. The rationale underlying this research is that by determining how microtubule properties are modulated by glutamylation, the contribution glutamylation makes, within the context of the tubulin code, to maintaining normal cytoskeletal function will be identified. To test the central hypothesis and, attain the overall objective, three specific aims will be addressed: 1) Determine the contribution glutamylation makes to centrosome stability. 2) Identify the mechanism by which glutamylation increases tolerance of microtubule stressors. 3) Determine how hyperglutamylation causes fertility defects. C. elegans mutants with reduced or hyper- glutamylated microtubules have been generated and light microscopic analyses of these worms will be used to dissect the function of glutamylation. Under aim one the focus will be on examining centrosome integrity and function by fixed and live microscopy. Under aims two and three analyses will investigate microtubule dynamics using EBP-2::GFP. The proposed research is innovative because genetically ablating glutamylation will allow the full suite of its functions to be elucidated in an intact multicellular organism. Completion of these aims will illuminate the role of glutamylation in modulating microtubule properties and clarify how it impacts centrosome function. This will be significant because it will allow the contribution glutamylation makes to the tubulin code with respect to regulating microtubule dynamics to be identified. Ultimately this knowledge has the potential to enhance our understanding of how normal microtubule function is impaired resulting in human disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$15,138 )
2024	2019	COLLEGE OF NEW JERSEY	2000 PENNINGTON RD	EWING	NJ	08618	MERCER	USA	Biomedical Research and Research Training	000	1	3/14/2024	NEW	-$15,138
														Subtotal = -$15,138

Issue Date FY: 2019 ( Subtotal = $304,958 )
2019	2019	COLLEGE OF NEW JERSEY, THE	2000 PENNINGTON RD	EWING	NJ	08628	MERCER	USA	Biomedical Research and Research Training	000	1	9/18/2019	NEW	$304,958
2019	2019	COLLEGE OF NEW JERSEY, THE	2000 PENNINGTON RD	EWING	NJ	08628	MERCER	USA	Biomedical Research and Research Training	001	1	9/19/2019	NEW	$0
														Subtotal = $304,958

Grand Total All Awards = $289,820

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Towards deciphering the tubulin code: Identifying the contribution glutamylation makes to regulation of microtubule dynamics

Award Number: R15GM135886

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/17/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2023

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