Regulators of Myofibroblast State Stability & Fibrotic Responsiveness of the Heart

肌成纤维细胞状态稳定性的调节因子

基本信息

批准号：
10634723
负责人：
Jennifer Michelle Davis
金额：
$ 63.45万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634723
关键词：
Address Angiotensin II Behavior Cardiac Cardiac Myocytes Cells Chromatin Chronic Chronic Disease Cicatrix Competence Cre driver Cues Data Deposition Development Disparate Engineering Environment Epigenetic Process Exposure to Extracellular Matrix Failure Fibroblasts Fibrosis Future Genetic Transcription Heart Heart Diseases Heart failure In Vitro Injury Intrinsic drive Kinetics Label Liver MAP Kinase Gene Maintenance Memory Molecular Mus Myofibroblast Nature Organ Pathologic Pattern Phenotype Phenylephrine Process Profibrotic signal Recovery Regulation Reporter Role Signal Transduction Skin Stimulus Stress Tamoxifen Therapeutic Therapeutic Intervention Tissues Ventricular Remodeling Work antifibrotic treatment coronary fibrosis epigenetic memory experience experimental study in vivo interest loss of function p38 Mitogen Activated Protein Kinase periostin pharmacologic preservation prevent response single-cell RNA sequencing targeted treatment wound healing

项目摘要

PROJECT SUMMARY Cardiac fibrosis is the pathologic development of scar tissue around the muscle cells of the heart. It occurs with nearly every form of heart disease and rapidly progresses the heart to failure. A fundamental cellular determinant of fibrosis is the transition of fibroblasts into myofibroblasts, which are the primary producers of fibrotic matrix. Notably, myofibroblast revert to quiescence as organs including the heart recover from some injuries and fibrosis resolves. New evidence from liver and skin suggests these deactivated myofibroblasts are primed to reactivate with enhanced fibrotic responsiveness and wound healing capabilities as a protective adaptation to future injury. This has never been examined in the heart, but our preliminary data suggests cardiac fibrosis more than doubles when recovered hearts experience a second bout of pathologic stress. Given heart disease develops from cumulative rounds of stress and recovery, cardiac myofibroblasts likely undergo multiple cycles of deactivation and reactivation providing impetus for delineating these processes and determining how they are regulated. Our previous work suggests that p38 MAPK regulates the stability of the myofibroblast phenotype and the heart's fibrotic response. Moreover, recent findings suggest p38 inhibition appears to deactivate myofibroblasts reverting them to quiescence. This finding suggests that we can use experimental p38 perturbations of the myofibroblast state to study its impact on the heart's fibrotic response. Hence two comprehensive specific aims will be used to examine the overarching hypothesis that p38 regulation of myofibroblast state stability and the kinetics and fate trajectory of deactivation underlies long-term fibrotic responsiveness of the heart. Here single cell RNA sequencing in combination with myofibroblast lineage reporter mice engineered with targeted gain or loss of p38 function will be used to determine: (Aim 1) the role of p38 in regulating myofibroblast deactivation and resolving cardiac fibrosis, and (Aim 2) the effects of p38 activity on deactivated cardiac myofibroblast reactivation, fibrotic responsiveness, and fibrotic memory. Together these aims will attempt (A) to define the process and regulation of cardiac myofibroblast deactivation and reactivation, (B) to identify compensatory responses to perturbations in myofibroblast activity, and (C) to identify the function of deactivated myofibroblasts, their epigenetic memories of injury, and their role in enhancing the heart's fibrotic responsiveness.

项目概要心脏纤维化是心脏肌肉细胞周围疤痕组织的病理发展。它几乎所有形式的心脏病都会发生这种情况，并迅速导致心脏衰竭。一个基本的纤维化的细胞决定因素是成纤维细胞向肌成纤维细胞的转变，肌成纤维细胞是纤维化的主要细胞。纤维化基质的生产者。值得注意的是，肌成纤维细胞与包括心脏在内的器官一样恢复静止状态从一些损伤中恢复并且纤维化得到解决。来自肝脏和皮肤的新证据表明这些失活的肌成纤维细胞准备重新激活，增强纤维化反应性和伤口愈合能力作为对未来伤害的保护性适应。这从来没有审视过内心，但我们的初步数据表明，当心脏恢复时，心脏纤维化会增加一倍以上第二轮病理应激。鉴于心脏病是由压力和压力的累积发展而来的在恢复过程中，心肌成纤维细胞可能会经历多个周期的失活和重新激活，从而提供描述这些流程并确定如何监管它们的动力。我们之前的工作表明 p38 MAPK 调节肌成纤维细胞表型和心脏纤维化的稳定性回复。此外，最近的研究结果表明 p38 抑制似乎会使肌成纤维细胞失活将它们恢复到静止状态。这一发现表明我们可以使用实验性 p38 扰动肌成纤维细胞状态以研究其对心脏纤维化反应的影响。因此两个综合具体目标将用于检验 p38 对肌成纤维细胞的调节这一总体假设状态稳定性以及失活的动力学和命运轨迹是长期纤维化的基础心脏的反应能力。这里单细胞 RNA 测序与肌成纤维细胞谱系相结合具有目标 p38 功能获得或丧失的基因工程报告小鼠将用于确定：（目标 1） p38 在调节肌成纤维细胞失活和解决心脏纤维化中的作用，以及（目标 2）效果 p38 活性对失活心肌成纤维细胞再激活、纤维化反应性和纤维化的影响记忆。这些目标将共同尝试 (A) 定义心脏的过程和调节。肌成纤维细胞失活和重新激活，（B）以确定对扰动的补偿反应肌成纤维细胞活性，以及 (C) 鉴定失活肌成纤维细胞的功能及其表观遗传损伤记忆及其在增强心脏纤维化反应性中的作用。