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.

项目总结 心脏纤维化是心脏肌肉细胞周围疤痕组织的病理性发展。它 几乎所有形式的心脏病都会发生，并迅速发展到心脏衰竭。一项基本原则 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，这是最主要的 纤维基质的生产者。值得注意的是，当器官包括心脏时，肌成纤维细胞恢复静止。 从一些损伤中恢复过来，纤维化也消失了。来自肝脏和皮肤的新证据表明 失活的肌成纤维细胞准备在纤维化反应增强和创伤后重新激活 治疗能力，作为对未来伤害的保护性适应。这一点从未在心脏中被检验过， 但我们的初步数据显示，当心脏恢复时，心脏纤维化会增加一倍以上。 第二轮病理性压力。鉴于心脏病是由累积的几轮压力和 恢复，心肌成纤维细胞可能经历多个周期的失活和再激活提供 描述这些过程并确定如何对其进行监管的动力。我们之前的工作 提示p38MAPK调节心肌成纤维细胞表型的稳定性和心脏纤维化 回应。此外，最近的研究结果表明，抑制p38似乎可以使肌成纤维细胞失活。 使它们回复到静止状态。这一发现表明，我们可以使用实验中的p38微扰 肌成纤维细胞状态，研究其对心脏纤维化反应的影响。因此有两个全面的 特定的目的将被用来检验p38对肌成纤维细胞的调控这一主要假设。 状态稳定性和失活的动力学和命运轨迹是长期纤维化的基础 心脏的响应性。单细胞RNA测序与肌成纤维细胞系相结合 P38功能的靶向获得或丢失的报告小鼠将被用来确定：(目标1) P38在调节肌成纤维细胞失活和消除心肌纤维化中的作用及(目标2)作用 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。这些目标将试图(A)定义心脏的过程和调节 肌成纤维细胞失活和再激活，(B)确定对扰动的代偿反应 肌成纤维细胞活性，以及(C)鉴定失活的肌成纤维细胞的功能，它们的表观遗传学 对受伤的记忆，以及它们在增强心脏纤维化反应中的作用。