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Research Project 2

研究项目2

基本信息

批准号：
10403256
负责人：
Su Chin Heo
金额：
$ 41.66万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10403256
关键词：
3-Dimensional ATAC-seq Address Affect Animals Architecture Biocompatible Materials Biology Biophysics Bioreactors Cells Center for Translational Science Activities ChIP-seq Chromatin Chromatin Structure Clinical Collaborations Coupled Cues Custom Disease Disease Progression Environment Epigenetic Process Exposure to Extracellular Matrix Gene Expression Gene Expression Profile Gene Order Genes Genetic Transcription Genome Genomics Goals Histone Acetylation Histone Deacetylase Inhibitor Histones Human Hydrogels Image In Vitro Knowledge Mechanics Modification Molecular Musculoskeletal Nanoscopy Nanostructures Nuclear Onset of illness Operative Surgical Procedures Pathology Pharmaceutical Preparations Phenotype Physical condensation Physical environment Physical therapy Physiological Play Proteins Protocols documentation RNA Recovery Research Research Project Grants Role Severities Site System Techniques Technology Tendinopathy Tendon Injuries Tendon structure Testing Therapeutic Therapeutic Intervention Therapeutic Uses Time Tissue Engineering Tissues Work achilles tendon cell behavior cost differential expression epigenetic drug epigenome epigenomic profiling genome-wide genome-wide analysis genomic locus histone methylation histone modification imaging modality improved inhibitor innovation joint loading mechanical load mechanical signal nanofiber nanoscale novel osteogenic repaired restoration single cell analysis soft tissue spatiotemporal superresolution imaging tissue degeneration tissue repair transcriptome sequencing treatment strategy ultra high resolution

项目摘要

PROJECT SUMMARY Achilles tendinopathy is a very prevalent and costly clinical problem. However, current surgical and drug strategies for tendon repair are limited, and non-surgical strategies to treat disease focus on stimulating tendon repair through physical therapy. Thus, there is an unmet clinical need to improve treatment strategies for tendon injuries. Tendon degeneration alters the chemo-physical environment and changes biophysical inputs to resident cells (called tenocytes). Both normal and aberrant phenotypes in tendon cells are defined by the dynamic spatio- temporal organization of their genome, and so it will be important to understand how 3D genome architecture in tendon cells changes with Achilles tendinopathy and how chemo-mechanical cues regulate transcriptional and chromatin profiles in degenerative cells to develop better therapeutic strategies for tendinopathies. Furthermore, the epigenetic mechanisms responsible for the tendon phenotype change in degenerative environments are underexplored. Epigenetic drugs are available and have been used for therapeutic purposes and likely also constitute a promising avenue for treatment of tendinopathies through manipulation of the epigenetic landscape and 3D chromatin architecture of tendon cells to lock in proper cell phenotype. To address these open questions, the overall goal of Research Project is to test our hypotheses that Achilles tendinopathy alters epigenetic landscape, 3D chromatin architecture, and transcriptional signatures in tenocytes impacting their phenotype, and that these alterations can be manipulated and restored via the combination of biophysical cues and epigenetic modifiers. The proposed work is significant as it will generate new knowledge about how changes in mechanical loading and mechano-signaling across the spectrum of disease impacts genome organization and tendon cell phenotype, and how these changes define disease progression and therapeutic interventions. Our Aims are: Aim 1: Determine how Achilles tendinopathy alters the nanoscale chromatin organization and accessibility landscape of tenocytes, impacting their phenotype. Aim 2: Identify whether biophysical cues and epigenetic modifiers restore ‘healthy’ tenocyte genome organization in ‘degenerative’ tenocytes to improve therapeutic strategies. The proposed research is innovative as we will use cutting-edge genome wide and single cell analyses to study, for the first time, how Achilles tendinopathy regulates nanoscale chromatin states and transcriptional activity, using single-cell based imaging and sequencing technologies. These studies will identify novel epigenetic mechanisms of Achilles tendon pathology and disease onset, new mechanical loading paradigms, and small epigenome-modifying molecules, providing critical and novel information to support new mechano-epigenetic strategies to improve the efficacy of targeted physical therapy protocols.

项目摘要跟腱病是一个非常普遍和昂贵的临床问题。然而，目前的手术和药物肌腱修复的策略是有限的，治疗疾病的非手术策略集中在刺激肌腱通过物理治疗进行修复。因此，改善肌腱损伤的治疗策略是一个未满足的临床需求。受伤肌腱退化改变了化学物理环境，改变了生物物理输入，细胞（tenocytes）。肌腱细胞的正常和异常表型都是由动态空间分布来定义的。他们的基因组的时间组织，因此，重要的是要了解三维基因组架构，跟腱细胞的变化与跟腱病和化学机械线索如何调节转录和在变性细胞中的染色质谱，以开发更好的治疗策略，肌腱病。此外，委员会认为，在退化环境中负责肌腱表型变化的表观遗传机制是探索不足表观遗传药物是可用的，并且已用于治疗目的，并且可能还构成了通过操纵表观遗传景观治疗肌腱病的有前途的途径和肌腱细胞的3D染色质结构以锁定适当的细胞表型。为了解决这些悬而未决的问题，研究项目的总体目标是检验我们的假设，即跟腱病改变了表观遗传学，景观，3D染色质结构，和肌腱细胞中影响其表型的转录特征，这些改变可以通过生物物理学线索和表观遗传学的结合来操纵和恢复。修饰语拟议的工作是重要的，因为它将产生新的知识，如何改变机械疾病谱中的负荷和机械信号传导影响基因组组织和肌腱细胞表型，以及这些变化如何定义疾病进展和治疗干预。我们的目标是：目的1：确定跟腱病如何改变纳米染色质组织和可及性肌腱细胞的景观，影响它们的表型。目的2：确定生物物理线索和表观遗传修饰剂在“退化”肌腱细胞中恢复“健康”肌腱细胞基因组组织以改善治疗效果战略布局拟议的研究是创新的，因为我们将使用尖端的全基因组和单细胞分析研究，第一次，跟腱病如何调节纳米染色质状态，转录活性，使用基于单细胞的成像和测序技术。这些研究将确定跟腱病理和疾病发作的新表观遗传机制，新的机械负荷范式和小表观基因组修饰分子，提供关键和新颖的信息，以支持新的机械表观遗传策略，以提高有针对性的物理治疗方案的疗效。