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.

项目概要跟腱病是一个非常普遍且昂贵的临床问题，然而，目前的手术和药物。肌腱修复策略有限，治疗疾病的非手术策略主要集中在刺激肌腱因此，改善肌腱治疗策略的临床需求尚未得到满足。肌腱退化改变了化学物理环境并改变了居民的生物物理输入。肌腱细胞中的正常和异常表型都是由动态空间定义的。基因组的时间组织，因此了解 3D 基因组结构如何在肌腱细胞随跟腱病的变化以及化学机械线索如何调节转录和退行性细胞中的染色质谱，以开发更好的肌腱病治疗策略。此外，退化环境中肌腱表型变化的表观遗传机制是表观遗传药物已经存在并已被用于治疗目的，也可能被用于治疗目的。构成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 染色质结构以锁定正确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，即跟腱病改变表观遗传肌腱细胞中影响其表型的景观、3D 染色质结构和转录特征，以及这些改变可以通过生物物理线索和表观遗传的结合来操纵和恢复拟议的工作意义重大，因为它将产生关于机械如何变化的新知识。多种疾病的负载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措施。目标 1：确定跟腱病如何改变纳米级染色质组织和可及性肌腱细胞的景观，影响其表型目标 2：确定生物物理线索和表观遗传是否存在。修饰剂恢复“退化”肌腱细胞中“健康”的肌腱细胞基因组组织，以改善治疗拟议的研究具有创新性，因为我们将使用尖端的全基因组和单细胞研究。首次分析研究跟腱病如何调节纳米级染色质状态和这些研究将使用基于单细胞的成像和测序技术来识别转录活性。跟腱病理学和疾病发生的新表观遗传机制、新机械负荷范式和小的表观基因组修饰分子，提供关键和新颖的信息来支持新的机械表观遗传策略可提高靶向物理治疗方案的功效。