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Elucidating Effects of Fibrosis on Aged Stem Cells with Dynamic Biomaterials

Award Number: K99AG071738
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/15/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2022

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Elucidating Effects of Fibrosis on Aged Stem Cells with Dynamic Biomaterials - PROJECT SUMMARY Despite the ubiquitous role of fibrosis in tissue dysfunction arising from aging and disease, no representative in vitro model of the fibrotic microenvironment exists. Fibrosis is characterized by excess extracellular matrix (ECM) deposition that stiffens the cellular microenvironment. Therefore, to model fibrosis in vitro, cell culture substrates that permit quantitative, dynamic tuning of matrix mechanics and composition are necessary. However, existing dynamic hydrogel culture platforms generally rely on chemistries that may be toxic to cells or that simultaneously change multiple parameters, making it difficult to assign causal relationships between altered matrix properties and cell fate changes. Fibrotic stiffening occurs in a wide range of tissues, including skeletal muscle. Along with increased fibrosis, the regenerative function of skeletal muscle decreases with aging. Muscle stem cells (MuSCs) are responsible for maintaining and repairing muscle throughout life and are known to be acutely mechanosensitive, losing their stem cell potential when cultured on stiff substrates. Thus, the stiffened, fibrotic microenvironment may contribute to the diminished regenerative capacity of aged MuSCs. The goal of this project is to develop an in vitro model of tissue fibrosis based on dynamic hydrogel biomaterials and to employ this model to identify molecular mechanisms of MuSC mechanosensing that are implicated in MuSC dysfunction in aging. The mentored phase of this proposal will provide advanced technical training in aging biology, transgenic mouse models, cellular traction force measurement, and machine learning approaches for bioinformatics. This training will enable an independent research program leveraging dynamic biomaterials to deconvolve the complex interactions of mechanical forces, matrix biochemistry, and cell-cell signaling that dictate the progression of aging and disease. Additional structured training in scientific writing, grantsmanship, and research management will facilitate the transition to independence, supported by a committee of faculty from the Stanford Schools of Medicine and Engineering. Aim 1 will optimize a synthetic hydrogel system that uses near-infrared light and bioorthogonal reactions to dynamically stiffen the gels, mimicking fibrosis. These hydrogels will be used to elucidate mechanisms of mechanosensing in MuSCs, using FRET-based force sensors and transgenic mouse models. Aim 2 will model muscle aging in vitro, using dynamically stiffening gels modified with ECM components characteristic of aging. Single cell RNA sequencing and machine learning bioinformatics approaches will identify unique mechanically regulated drivers of cell fate that reduce MuSC regenerative potential in aging. Aim 3 will develop novel materials for 3D cell culture with dynamic tuning of viscoelastic properties to establish the first human model of muscle “aging in a dish.” This project stands to identify new therapeutic targets to improve muscle function with aging and to develop engineered platforms to study numerous heritable diseases and aging in diverse tissues.


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: 2023 ( Subtotal = -$122,545 )
2023	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	003	2	7/13/2023	NON-COMPETING CONTINUATION	-$120,166
2023	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	001	2	1/24/2023	NON-COMPETING CONTINUATION	$0
2023	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	000	2	12/19/2022	NON-COMPETING CONTINUATION	$0
2023	2021	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	002	1	7/13/2023	NEW	-$2,379
														Subtotal = -$122,545

Issue Date FY: 2022 ( Subtotal = $120,166 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	000	2	7/26/2022	NON-COMPETING CONTINUATION	$120,166
														Subtotal = $120,166

Issue Date FY: 2021 ( Subtotal = $120,166 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	000	1	8/13/2021	NEW	$120,166
														Subtotal = $120,166

Grand Total All Awards = $117,787

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Elucidating Effects of Fibrosis on Aged Stem Cells with Dynamic Biomaterials

Award Number: K99AG071738

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/15/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2022

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