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Tubulin modifications and cytoskeletal alterations in aging

Award Number: R21AG076470
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Tubulin modifications and cytoskeletal alterations in aging - Project Summary Remarkably, our understanding of the mechanisms that lead to cytoskeletal alterations and the phenotypic impact of these alterations in aging cells remains very limited. We have identified and begun characterizing key proteins required to maintain normal nuclear morphology, including two novel proteins (LRRC49 and C11orf49) that assemble into a tubulin poly-glutamylase (TPG) complex. We have recently shown that each protein regulates both tubulin glutamylation and nuclear morphology, and ablation of these genes alters post- translational modifications (PTM) of tubulin, cytoskeletal networks, and nuclear shape. Since similar cytoskeletal and nuclear defects are also observed in cells obtained from patients with the premature aging syndrome, Hutchinson-Gilford progeria syndrome (HGPS), this prompted us to hypothesize that specific defects in PTMs and microtubule networks could be associated with aging. Furthermore, it is known that levels of SUN1, a component of the LINC (Linkers of Nucleoskeleton and Cytoskeleton) complex that connects the cytoskeleton and the nucleoskeleton, are altered during normal and premature aging. However, it is unknown whether altered SUN1 levels are a cause or consequence of aging. We will pursue two Aims that combine biochemical and cell biological approaches to (1) investigate a global role for defects in microtubule networks and alterations in tubulin glutamylation and SUN1 levels during physiological aging and in progeroid cells, and (2) identify how defects associated with normal and premature aging are translated into genome-wide changes in chromatin topology. Here, we will specifically focus on how the TPG and SUN1 protein globally regulate microtubule networks and nuclear assembly during aging. Our studies will address fundamental questions related to the role of SUN1 and tubulin modifications in nuclear shape changes and in physiological and pathological models of aging, and our studies will determine whether these alterations are a cause or consequence of aging. Our studies will also provide insights into the changes in chromatin topology sustained by cells that age through normal or pathological mechanisms.


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: 2025 ( Subtotal = $0 )
2025	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	000	2	1/31/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $211,875 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	000	2	1/30/2024	NON-COMPETING CONTINUATION	$190,688
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	001	2	6/12/2024	NON-COMPETING CONTINUATION	$21,187
														Subtotal = $211,875

Issue Date FY: 2023 ( Subtotal = $254,250 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	000	1	2/10/2023	NEW	$254,250
														Subtotal = $254,250

Grand Total All Awards = $466,125

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Tubulin modifications and cytoskeletal alterations in aging

Award Number: R21AG076470

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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