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Role of LINC-mediated Mechanosignaling in MSC Aging

Award Number: R01AG059923
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Role of LINC-mediated Mechanosignaling in MSC Aging - Project Summary Mesenchymal stem cells (MSC) in bone marrow provide regenerative capacity for bone, replacing and reinforcing the skeleton at load bearing sites. When we age or in prolonged bedrest, MSCs lose their regenerative potential, often measured by their proliferative and differentiation capacity. This loss of MSC health causes osteoporosis and delayed healing, ultimately resulting in decreased quality of life and increased medical costs. A fundamental knowledge gap preventing effective therapies in aging and MSC related regenerative medicine is how aging and bedrest impedes MSC health. The nucleus, central to all cellular activity, relies on both mechanical input as well as its molecular transducers to regulate intra-nuclear chromatin organization that ultimately determine cell function and fate. Thus, failure to transmit this information to the nucleus would lead to the breakdown of these processes. Here, we ask if aging is a process that limits information flow into the nucleus, ultimately diminishing its organizational capacity and responsiveness to outside stimuli. As we will show, disabling the mechanical connection between cytoskeleton and nucleus facilitated by Linker of Nucleoskeleton and Nucleoskeleton (LINC) complexes, impairs mechanosensitivity by affecting βcatenin and YAP/TAZ signaling. This leads to decreased proliferation and differentiation of mesenchymal stem cells. Our principal hypothesis is that loss of LINC-connectivity significantly contributes to MSC aging by disrupting nuclear mechanotransduction. Through this revision submitted in response to [PA16-442] - Changes in Cellular Architecture During Aging (R01), we will address our principal hypothesis through two specific aims, each using a distinct hypotheses to examine how inhibiting LINC complex function as well as how aging related loss of LINC complex limits MSC mechanosignaling of known mechanotransducers βcatenin and YAP/TAZ. We will further determine the force-induced mechanisms of how sustained physical activity protects LINC complex expression to augment MSC and bone mechanosignaling within the context of aging. If successful, we will establish, for the first time, a mechanistic understanding of how loss of LINC complex drives decreased mechanosensory capability in aging. Completion of these aims will provide research communities with (1) efficacy of LIV based regenerative modalities that improve LINC-mediated mechanosignaling and (2) foundational structure-function relationship data in healthy and aged stem cells.


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 = $280,231 )
2024	2024	BOISE STATE UNIVERSITY	1910 UNIVERSITY DR	BOISE	ID	83725	ADA	USA	Aging Research	000	5	1/29/2024	NON-COMPETING CONTINUATION	$252,208
2024	2024	BOISE STATE UNIVERSITY	1910 UNIVERSITY DR	BOISE	ID	83725	ADA	USA	Aging Research	001	5	6/14/2024	NON-COMPETING CONTINUATION	$28,023
														Subtotal = $280,231

Issue Date FY: 2023 ( Subtotal = $280,602 )
2023	2023	BOISE STATE UNIVERSITY	1910 UNIVERSITY DR	BOISE	ID	83725	ADA	USA	Aging Research	000	4	4/18/2023	NON-COMPETING CONTINUATION	$280,602
														Subtotal = $280,602

Issue Date FY: 2022 ( Subtotal = $353,672 )
2022	2022	BOISE STATE UNIVERSITY	1910 UNIVERSITY DR	BOISE	ID	83725	ADA	USA	Aging Research	002	3	6/9/2022	NON-COMPETING CONTINUATION	$28,096
2022	2022	BOISE STATE UNIVERSITY	1910 UNIVERSITY DR	BOISE	ID	83725	ADA	USA	Aging Research	001	3	2/3/2022	SUPPLEMENT FOR EXPANSION	$72,716
2022	2022	BOISE STATE UNIVERSITY	1910 UNIVERSITY DR	BOISE	ID	83725	ADA	USA	Aging Research	000	3	2/1/2022	NON-COMPETING CONTINUATION	$252,860
														Subtotal = $353,672

Issue Date FY: 2021 ( Subtotal = $402,484 )
2021	2021	BOISE STATE UNIVERSITY	1910 UNIVERSITY DR	BOISE	ID	83725	ADA	USA	Aging Research	001	1	12/11/2020	SUPPLEMENT FOR EXPANSION	$153
2021	2021	BOISE STATE UNIVERSITY	1910 UNIVERSITY DR	BOISE	ID	83725	ADA	USA	Aging Research	000	1	11/13/2020	SUPPLEMENT FOR EXPANSION	$24,086
2021	2021	BOISE STATE UNIVERSITY	1910 UNIVERSITY DR	BOISE	ID	83725	ADA	USA	Aging Research	002	2	2/17/2021	NON-COMPETING CONTINUATION	$378,245
														Subtotal = $402,484

Issue Date FY: 2020 ( Subtotal = $281,613 )
2020	2020	BOISE STATE UNIVERSITY	1910 UNIVERSITY DR	BOISE	ID	83725	ADA	USA	Aging Research	000	1	2/28/2020	NEW	$281,613
														Subtotal = $281,613

Grand Total All Awards = $1,598,602

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Role of LINC-mediated Mechanosignaling in MSC Aging

Award Number: R01AG059923

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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