ELUCIDATING EFFECTS OF FIBROSIS ON AGED STEM CELLS WITH DYNAMIC BIOMATERIALS - PROJECT SUMMARY DESPITE THE…

Assistance award details

Assistance award identifier

ASST_NON_R00AG071738_075

FAIN

R00AG071738

Recipient

TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$864,566

Period

Aug 15, 2021 – Dec 31, 2025

Fiscal year

2023

Place of performance state

PA

Source file

FY2023_All_Assistance_Full_20261006.zip

Description

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 AGIN