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Molecular Mechanisms of Telomere Length Homeostasis

Award Number: R35GM149572
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: 04/13/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Molecular Mechanisms of Telomere Length Homeostasis - Project Summary Telomeres ensure genome integrity by facilitating chromosome end replication through telomerase, the activity of which enables cellular proliferation. Uncontrolled proliferation as may occur in cancer cells requires hyper-activation of telomere-extension activity. Conversely, lack of telomere extension results in degenerative disorders or premature aging. Critical to telomere structure and function, the conserved multifunctional shelterin complex associates with telomeres to coordinate multiple telomere activities. The long-term objective of our NIGMS MIRA research program is to determine, at the atomic resolution, molecular mechanisms of telomere length homeostasis through comprehensive biochemical, structural, and functional characterizations of the telomeric shelterin complex, shelterin-telomerase interactions, and telomerase biogenesis. Mutations in telomerase subunits or shelterin components have been increasingly linked to cancer and premature aging. Shelterin complex and shelterin-telomerase interactions play essential roles in regulating synthesis of telomeric DNA repeats and defining telomere lengths that support or restrict cell proliferation. Our recent efforts have achieved the conceptual advancement on the role of shelterin bridge, rather than individual shelterin component per se, in regulating telomere length and the landmark determination of the atomic views of shelterin bridge assembly process by x-ray crystallography. Our accumulated expertise and prior success position us to deepen our investigations. In the next five years, we aim to address the following three fundamental questions in the field: 1) Elucidate the biochemical and structural basis of the assembly of whole fission yeast shelterin complex and its role in telomere length control; 2) Determine the mechanistic basis of shelterin disassembly; 3) Determine the structural basis of telomerase RNA folding quality control mechanism by Pof8 complex. Accomplishment of the proposed studies will provide new and significant mechanistic insights into the maintenance of our chromosome ends and set up the foundation for the development of new therapeutic approaches against diseases caused by telomere dysfunction, such as premature aging.


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 = $392,500 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	001	3	4/11/2025	NON-COMPETING CONTINUATION	$392,500
2025	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	000	2	11/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $392,500

Issue Date FY: 2024 ( Subtotal = $639,478 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	001	2	5/13/2024	SUPPLEMENT FOR EXPANSION	$246,978
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	002	2	6/21/2024	NON-COMPETING CONTINUATION	$39,250
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	000	2	3/1/2024	NON-COMPETING CONTINUATION	$353,250
														Subtotal = $639,478

Issue Date FY: 2023 ( Subtotal = $392,500 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	000	1	4/12/2023	NEW	$392,500
														Subtotal = $392,500

Grand Total All Awards = $1,424,478

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Molecular Mechanisms of Telomere Length Homeostasis

Award Number: R35GM149572

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: 04/13/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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