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Role of Desumoylase SENP6 in Joint Aging and Osteoarthritis Development

Award Number: R01AG061086
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2019
PERIOD OF PERFORMANCE END DATE: 09/30/2025

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Role of Desumoylase SENP6 in Joint Aging and Osteoarthritis Development - PROJECT SUMMARY For decades, it has been known that the inflammatory and catabolic environment in the joints accelerates oste- oarthritis (OA) development. However, current OA therapies that inhibit this environment are not curative, as they do not target the underlying cause of such an environment. It was recently shown that senescent articular chondrocytes (ACs) are a major source of inflammatory and catabolic factors. Last year, it was reported that eliminating senescent ACs can alleviate the progression of age-related and post-traumatic OA in mice. While this suggests a potential treatment avenue, ideally, we would also identify the root causes (i.e. the pathways) that lead to AC senescence, and target those to prevent or slow the transition to senescence in the first place. Our long-term goal is to examine the mechanisms that lead to AC senescence, so that strategies can be devel- oped for prevention and/or treatment of OA. To that end, data from a genome-wide association study (arcO- GEN Consortium, 2012) showed a strong association of OA with SENP6, which is an enzyme (desumoylase) that reverses SUMO modifications on specific protein targets. We found this intriguing, because sumoylation is an enzymatic pathway that has been associated with both the stress response and the aging process, and is potentially druggable. My lab has reported the correlations among the SENP6 pathway, cell senescence, and stress response in skeletal progenitors. Also, we showed that this occurs partially via over-sumoylation of TRIM28, an epigenetic regulator associated with senescence. Moreover, our preliminary work found that SENP6 loss in cartilage accelerated AC senescence and OA in mice, providing a rationale for further examin- ing the role of SENP6. The hypothesis is that SENP6 reduces OA susceptibility by suppressing AC senes- cence induced by stress response and epigenetic alterations. To test this hypothesis, our first goal is to deter- mine the future viability of SENP6 as a possible target for treatment; we will examine the extent to which gain of SENP6 function reduces OA progression. Next, because our preliminary work suggested an interplay be- tween SENP6 stability and stress response, the second goal is to determine how stress induces SENP6 degra- dation and how the underlying mechanism affects AC senescence. Our third goal is to identify SENP6-orches- trated epigenetic alterations and their role in AC senescence. This is inspired by the facts that epigenetic alter- ations are a hallmark of aging and that our and other's findings suggest a potential role for the SENP6–TRIM28 axis in the epigenetic regulation of gene expression and inflammation. It is expected that this proposed work will have a broad impact by uncovering a new mechanism that connects the sumoylation pathways to stress response, epigenetic alterations, senescence, joint aging, and OA. These results will form a basis for develop- ing new OA treatments by inhibiting AC senescence through selective modulation of sumoylation-related path- ways, e.g., by increasing SENP6 level or activity.


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: 2026 ( Subtotal = $0 )
2026	2023	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Aging Research	000	5	3/25/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Aging Research	000	5	4/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $498,490 )
2023	2023	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Aging Research	001	5	4/5/2023	NON-COMPETING CONTINUATION	$498,490
2023	2022	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Aging Research	000	4	10/24/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $498,490

Issue Date FY: 2022 ( Subtotal = $498,490 )
2022	2022	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Aging Research	000	4	4/14/2022	NON-COMPETING CONTINUATION	$498,490
														Subtotal = $498,490

Issue Date FY: 2021 ( Subtotal = $498,490 )
2021	2021	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Aging Research	000	3	3/19/2021	NON-COMPETING CONTINUATION	$498,490
														Subtotal = $498,490

Issue Date FY: 2020 ( Subtotal = $498,490 )
2020	2020	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Aging Research	000	2	5/15/2020	NON-COMPETING CONTINUATION	$498,490
														Subtotal = $498,490

Issue Date FY: 2019 ( Subtotal = $534,964 )
2019	2019	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Aging Research	000	1	7/3/2019	NEW	$498,490
2019	2019	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Aging Research	001	1	8/10/2019	NEW	$36,474
														Subtotal = $534,964

Grand Total All Awards = $2,528,924

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Role of Desumoylase SENP6 in Joint Aging and Osteoarthritis Development

Award Number: R01AG061086

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2019

PERIOD OF PERFORMANCE END DATE: 09/30/2025

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