Tuesday, July 1, 2025 7/1/2025

International Registry for Werner Syndrome

Award Number: R01CA210916
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/04/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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International Registry for Werner Syndrome - Project Summary The International Registry of Werner Syndrome recruits cases of Werner syndrome (WS) and a range of other segmental progeroid syndromes from around the world with the goal of elucidating underlying mechanisms of accelerated aging. Detailed clinical information, the results of genetic analyses, and biological specimens are made available to a wide range of qualified geroscientists. In this application, we propose to extend our previous studies to include systematic genome-wide searches for the genetic variants responsible for the 78 progeroid cases that we have so far been unable to genetically characterize. An additional important extension of our research agenda is to initiate translational research that can lead to potential therapeutic agents. We will employ a combination of next generation sequencings, array CGH, and Sanger sequencing, followed by confirmatory Western analysis and quantitative PCR. These approaches have successfully identified novel pathogenic variants of WRN (a DNA helicase), LMNA (a component of nuclear structure), POLD1 (DNA polymerase delta), SPRTN (recruiter of DNA polymerase), ERCC4 (nucleotide excision repair), CTC1 (telomere replication), MDM2 (an inhibitor of P53) and SAMHD1 (regulation of dNTP pools). These loci highlight major roles for genome instability, now widely accepted as one of the hallmarks of aging. We also made progress in the identification of disease mutations that suggest other mechanisms of accelerated aging, such as BSCL2 (lipid droplet formation) and SMAD4 (intracellular signaling of a component of SASP, TGFβ). As indicated above, we will pursue translational research with the potential for the development of ameliorative therapies for our progeroid patients. Based on our previous studies, our collaborator, Dr. Yokote Koutaro at the Japanese Werner Consortium, is evaluating the efficacy of an NAD intermediate and an mTOR inhibitor, metformin, in WS patients. We shall begin independent studies of the effects of suppressors of chronic inflammation, namely Janus kinase (JAK) inhibitors, in cultures from WS patients and controls. This effort was motivated by our findings that SMAD4 mutant fibroblasts exhibited increased accumulation of DNA damage and that WRN mutant fibroblasts showed elevated SMAD4 expressions and dramatically higher levels of SASP compared to control cells, suggesting that a synergy of persistent DNA damage and inflammation may be one of the common key mechanisms leading to the accelerated aging. Concordant experiments will explore the effects of these novel therapeutic targets with high throughput screening of cell cultures from patients with other progeroid syndromes. An initial small scale experiment involving siRNA screening has revealed that siRNAs and drugs that alter the intranuclear dNTP concentration are able to modulate the cellular disease phenotypes of POLD1 mutants. Larger scale siRNA screening will be employed to identify additional novel relevant target pathways as well as previously unknown functional interactions of progeroid genetic loci.


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 = $371,713 )
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	001	9	6/13/2025	NON-COMPETING CONTINUATION	$37,170
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	000	9	2/13/2025	NON-COMPETING CONTINUATION	$334,543
														Subtotal = $371,713

Issue Date FY: 2024 ( Subtotal = $353,128 )
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	000	8	1/26/2024	NON-COMPETING CONTINUATION	$334,543
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	001	8	4/17/2024	NON-COMPETING CONTINUATION	$18,585
														Subtotal = $353,128

Issue Date FY: 2023 ( Subtotal = $364,279 )
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	000	7	2/20/2023	NON-COMPETING CONTINUATION	$364,279
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	001	7	4/4/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $364,279

Issue Date FY: 2022 ( Subtotal = $371,713 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	002	6	2/4/2022	COMPETING CONTINUATION	$371,713
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	004	6	4/18/2022	COMPETING CONTINUATION	$134,149
2022	2021	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	003	5	4/18/2022	SUPPLEMENT FOR EXPANSION	-$134,149
2022	2021	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	000	5	1/20/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2020	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	001	5	1/27/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $371,713

Issue Date FY: 2021 ( Subtotal = $217,700 )
2021	2021	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	000	5	4/6/2021	SUPPLEMENT FOR EXPANSION	$217,700
														Subtotal = $217,700

Issue Date FY: 2020 ( Subtotal = $353,419 )
2020	2020	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	000	5	4/23/2020	NON-COMPETING CONTINUATION	$353,419
														Subtotal = $353,419

Issue Date FY: 2019 ( Subtotal = $342,815 )
2019	2019	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	000	4	4/1/2019	NON-COMPETING CONTINUATION	$342,815
														Subtotal = $342,815

Issue Date FY: 2018 ( Subtotal = $353,419 )
2018	2018	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	000	3	4/20/2018	NON-COMPETING CONTINUATION	$353,419
														Subtotal = $353,419

Issue Date FY: 2017 ( Subtotal = $353,419 )
2017	2017	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	000	2	4/26/2017	NON-COMPETING CONTINUATION	$318,077
2017	2017	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	001	2	6/7/2017	NON-COMPETING CONTINUATION	$35,342
														Subtotal = $353,419

Issue Date FY: 2016 ( Subtotal = $353,419 )
2016	2016	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Cancer Biology Research	000	1	5/18/2016	NEW	$353,419
														Subtotal = $353,419

Grand Total All Awards = $3,435,024

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International Registry for Werner Syndrome

Award Number: R01CA210916

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/04/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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