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Elucidating Effects of Fibrosis on Aged Stem Cells with Dynamic Biomaterials

用动态生物材料阐明纤维化对衰老干细胞的影响

基本信息

批准号：
10299996
负责人：
Christopher Matthew Madl
金额：
$ 12.02万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10299996
关键词：
3-Dimensional Acute Adhesives Aging Attention Biochemical Biochemistry Biocompatible Materials Bioinformatics Biological Models Biology of Aging Biophysics Cell Culture Techniques Cells Cessation of life Characteristics Chemistry Chronic Complex Coupled Cues Cultured Cells Data Defect Deposition Development Disease Engineering Engraftment Environment Exhibits Extracellular Matrix Extracellular Matrix Proteins Faculty Failure Fibrosis Fluorescence Resonance Energy Transfer Functional disorder Gel Generations Goals Health Heritability Histology Human Hydrogels Impairment In Vitro Individual Inflammation Lead Life Light Machine Learning Measurement Measures Mechanics Mentors Modeling Molecular Molecular Target Mus Muscle Muscle function Muscle satellite cell Muscular Atrophy Natural regeneration Organ failure Pathogenesis Pathologic Pharmaceutical Preparations Phase Physiological Play Property Protein Engineering Reaction Regenerative capacity Research Research Proposals Role Skeletal Muscle Stromal Cells Structure System Time Tissue Model Tissues Traction Training Transgenic Mice Transplantation Writing adult stem cell aged aging population base bioluminescence imaging crosslink force sensor genetic approach human model improved in vitro Model in vivo induced pluripotent stem cell insight intercellular communication mechanical force mechanical properties mechanotransduction medical schools mouse model muscle aging new therapeutic target novel novel therapeutics p38 Mitogen Activated Protein Kinase programs regeneration function regeneration potential repaired response rho GTP-Binding Proteins single-cell RNA sequencing small molecule inhibitor stem cell function stem cell niche stem cell population stem cells three dimensional cell culture three-dimensional modeling tissue regeneration tissue repair transcriptomics viscoelasticity wound healing

项目摘要

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.

项目总结