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Mechanogenetics: An Integrated Approach to Aging in Muscle Dysfunction

Award Number: R01AG045428
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2013
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Mechanogenetics: An Integrated Approach to Aging in Muscle Dysfunction - Project Summary Cardiac performance declines with age, but genetic variation within a population makes it difficult to identify the conserved aging mechanisms that negatively impact mechanical function, i.e. mechanogenetics. Over the past 5 years, we have studied cardiac function of the rapidly aging Drosophila melanogaster across many laboratory fruit fly strains. We found that fly strains with age-dependent and heart-specific vinculin up- regulation use it to reinforce and stiffen their costameres and intercalated discs, which helps maintain the crystallinity of their sarcomere lattice and improves contractility. At the cardiomyocyte level, maintaining inter- myofilament spacing prolongs wall shortening velocity and fractional shortening, and systemically, it extends lifespan. Fly strains with decreased basement membrane (BM) protein expression, e.g. laminin, also exhibit similar systemic benefits but due to thinner extracellular matrix, which improves cell-cell coupling between adjacent myocyte layers; importantly, both vinculin up-regulation and BM down-regulation with age appear conserved up through non-human primates. Together these data suggest a new inside-outside aging paradigm that prolongs heart function, i.e. a robust internal contractile apparatus with limited extracellular connections to BM. In this grant application, we propose further aims to determine how these intracellular and extracellular heart perturbations act combinatorially to alter function across cellular-, tissue-, and organ-levels. Preliminary assessments in transgenic fly strains suggest that more efficient cardiomyocyte contraction, may improve substrate utilization and oxygen consumption within fly hearts, and subsequently organ perfusion and systemic metabolism, and better health- and lifespan. In light of this paradigm and the challenges that mechanogenetics present, we have developed new biological and analytical tools for this grant that will improve the feasibility of assessing the age-related mechanical differences of Drosophila myocardium between wild-type and transgenic lines. Thus, this on-going work will continue to improve our understanding of the inside-outside aging paradigm.


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 = $0 )
2024	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	10	8/21/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $395,630 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	10	6/3/2022	NON-COMPETING CONTINUATION	$395,630
														Subtotal = $395,630

Issue Date FY: 2021 ( Subtotal = $395,018 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	9	6/16/2021	NON-COMPETING CONTINUATION	$395,018
														Subtotal = $395,018

Issue Date FY: 2020 ( Subtotal = $405,677 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	8	5/22/2020	NON-COMPETING CONTINUATION	$405,677
														Subtotal = $405,677

Issue Date FY: 2019 ( Subtotal = $412,568 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	7	5/24/2019	NON-COMPETING CONTINUATION	$412,568
														Subtotal = $412,568

Issue Date FY: 2018 ( Subtotal = $401,545 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	001	6	9/15/2018	COMPETING CONTINUATION	$401,545
2018	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	5	8/1/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $401,545

Issue Date FY: 2017 ( Subtotal = $278,486 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	002	5	6/14/2017	NON-COMPETING CONTINUATION	$27,849
2017	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	001	5	3/28/2017	NON-COMPETING CONTINUATION	$250,637
2017	2015	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	3	10/25/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $278,486

Issue Date FY: 2016 ( Subtotal = $281,502 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	4	4/26/2016	EXTENSION WITH OR WITHOUT FUNDS	$281,502
														Subtotal = $281,502

Issue Date FY: 2015 ( Subtotal = $275,668 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	3	6/30/2015	NON-COMPETING CONTINUATION	$275,668
														Subtotal = $275,668

Issue Date FY: 2014 ( Subtotal = $286,600 )
2014	2014	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	2	7/24/2014	NON-COMPETING CONTINUATION	$286,600
														Subtotal = $286,600

Issue Date FY: 2013 ( Subtotal = $302,497 )
2013	2013	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	1	7/19/2013	NEW	$302,497
														Subtotal = $302,497

Grand Total All Awards = $3,435,191

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Mechanogenetics: An Integrated Approach to Aging in Muscle Dysfunction

Award Number: R01AG045428

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2013

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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