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

• 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
• 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

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.

项目摘要 心脏纤维化是心脏肌肉细胞周围疤痕组织的病理发育。它 发生几乎每种形式的心脏病，并迅速发展为失败。基本 纤维化的细胞决定因素是成纤维细胞向肌纤维细胞的过渡，这是主要的 纤维化基质的生产者。值得注意的是，肌纤维细胞恢复为包括心脏在内的器官 从一些损伤中恢复，纤维化解决。肝脏和皮肤的新证据表明这些 停用的肌纤维细胞被启动以增强的纤维化反应和伤口重新活化 治愈能力是对未来伤害的保护作用。这从未在心中进行检查过， 但是我们的初步数据表明，当恢复心脏经历时，心脏纤维化倍增 第二次病理性压力。鉴于心脏病是由于压力的累积回合而发展 恢复，心脏肌纤维细胞可能会经历多个停用和重新激活的周期 推动描述这些过程并确定如何调节这些过程的动力。我们以前的工作 建议p38 MAPK调节肌纤维细胞表型的稳定性和心脏的纤维化 回复。此外，最近的发现表明p38抑制似乎会失活的肌纤维细胞 将它们恢复到静止。这一发现表明我们可以使用实验p38 肌纤维细胞状态研究其对心脏纤维化反应的影响。因此，两个全面 具体目的将用于检验p38肌纤维细胞调节的总体假设 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。在这里，单细胞RNA测序与肌纤维细胞谱系结合 以针对性的增益或p38功能丧失设计的记者小鼠将使用：（ AIM 1） p38在调节肌纤维细胞失活和解决心脏纤维化中的作用，（AIM 2）影响 p38在停用心脏肌纤维细胞重新激活，纤维化反应性和纤维化的活性 记忆。这些目标将共同尝试（a）定义心脏的过程和调节 肌纤维细胞停用和重新激活，（b）确定对扰动的补偿性反应 肌纤维细胞活性，（c）确定失活的肌纤维细胞的功能，其表观遗传学 伤害的记忆及其在增强心脏纤维化反应性方面的作用。