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且昂贵的临床问题。但是，目前的手术和药物肌腱修复的策略受到限制，非手术策略治疗疾病专注于刺激肌腱通过物理疗法修复。那是没有满足的临床需要改善肌腱的治疗策略受伤。肌腱发育改变了化学物理环境，并向居民改变生物物理输入细胞（称为Tenocyttes）。肌腱细胞中正常和异常表型均由动态空间定义其基因组的临时组织，因此了解3D基因组体系结构如何肌腱细胞随跟腱疾病而变化，化学机械提示如何调节转录和退化细胞中的次数谱，以开发出更好的肌腱病治疗策略。此外，负责退化环境中肌腱表型变化的表观遗传机制是尚未得到充实的。可以使用表观遗传药物，并且已用于治疗目的，也可能构成通过操纵表观遗传景观来治疗肌腱病的承诺大道肌腱细胞的3D染色质结构锁定在适当的细胞表型中。要解决这些开放问题，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学景观，3D染色质体系结构和带有影响其表型的内科细胞的转录特征，可以通过生物物理提示和表观遗传学的组合来操纵和恢复这些改变修饰符。提出的工作很重要，因为它将为机械变化产生新的知识疾病范围内的负载和机械信号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的进展和治疗性干预措施。我们的目标是： AIM 1：确定跟腱病如何改变纳米级染色质组织和可及性弯曲细胞的景观，影响其表型。目标2：确定生物物理提示和表观遗传学是否修饰符恢复“退化”纳科细胞中的“健康” Tenocyte基因组组织，以改善治疗策略。拟议的研究具有创新性，因为我们将使用尖端的基因组宽和单细胞分析首次研究跟腱疾病如何调节纳米级染色质状态和转录活性，使用基于单细胞的成像和测序技术。这些研究将确定阿喀琉斯肌腱病理学和疾病发作的新型表观遗传机制，新的机械负荷范式和小表观基因组修改分子，提供关键和新颖的信息以支持新的信息提高靶向物理治疗方案效率的机械景观策略。