Innate immune response signaling in cardiac injury healing

心脏损伤愈合中的先天免疫反应信号

• 批准号: 10544189
• 负责人: Jeffery D Molkentin
• 金额: $ 60.52万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544189
• 关键词: Acute; Adult; Affect; Agonist; Area; Atherosclerosis; Bacteria; Basic Science; Biology; Cardiac; Cardiac Myocytes; Cell Therapy; Cell membrane; Cells; Cicatrix; Communication; Compensation; Complement Activation; DNA; Data; Dendritic Cells; Disease; Effectiveness; Endosomes; Fibroblasts; Gene Targeting; Genetic; Goals; Heart; Heart Diseases; Heart Injuries; Heart failure; Immune response; Immune signaling; Immune system; Infarction; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injections; Injury; Innate Immune Response; Interferons; Ischemia; Longevity; Macrophage; Mediating; Mus; Muscle Cells; Myocardial Infarction; Myocardial Ischemia; Natural regeneration; Nature; Neurosecretory Systems; Pathway interactions; Patients; Pattern recognition receptor; Performance; Process; Production; Proteins; RNA; Receptor Signaling; Rejuvenation; Reperfusion Injury; Reperfusion Therapy; Research; Resolution; Rodent Model; Signal Pathway; Signal Transduction; Stimulator of Interferon Genes; System; TLR2 gene; TLR3 gene; TLR4 gene; TLR5 gene; TLR6 gene; TLR7 gene; TLR8 gene; Therapeutic; Tissue Expansion; Tissues; Toll-like receptors; Virus; Western World; Zymosan; adult stem cell; cardiac repair; cardiovascular health; direct application; functional improvement; fungus; healing; heart damage; in vivo; injured; innate immune mechanisms; ischemic injury; mouse genetics; neutrophil; novel; novel therapeutics; physical property; programs; recruit; regenerative; response; response to injury; stem cells

Abstract Myocardial infarction (MI) due to underlying atherosclerosis is the leading disease sequela that precipitates heart failure in the Western world. Our ability to treat these patients and their heart failure has not progressed beyond a mild 20-30% extension in life span realized some 3 decades ago with neuroendocrine-based management [1]. New therapeutic avenues are needed, the most dramatic of which would be directly generating new cardiomyocyte to regenerate the damaged area of heart tissue. Previous attempts to regenerate the heart through new myocyte production have not been successful despite more than 18 years of research using adult progenitor cells. However, studies with cardiac progenitor cells in rodent models did show a functional benefit to the MI-injured heart, although we now understand that this is not due to significant new myocyte production. Instead we and others have identified a novel mechanism of benefit whereby injected progenitor cells have a rejuvenating effect on the MI-injured heart through refinement of the immune response. Indeed, we have shown that cell therapy injections that flank the recently injured area of the heart from ischemia- reperfusion (7 days later) can optimize healing, reduce infarct area expansion and augment scar borderzone physical properties (Vagnozzi et al., 2020, Nature). These beneficial effects were mediated through selective macrophage subtype activity in the heart, underscoring the importance of the immune response in cardiovascular health and infarct healing and compensation. Here we propose the hypothesis that selective innate immune response signaling pathways, and macrophage subtype polarization can be exploited to help heal the heart. Our more specific hypothesis is that therapy has an underlying protective component through Toll-like receptor (TLR) signaling in both cardiomyocytes and macrophages, and this can be therapeutically exploited to polarize the immune response for better healing. The specific aims are: AIM #1, To examine the mechanism of innate immune signaling in the heart through TLR signaling. AIM #2, To inducibly alter macrophage subtypes in the heart to reprogram the innate immune response and healing dynamics by cell therapy. AIM #3, To determine how fibroblasts communicate with macrophage subtypes in the post-MI injured heart to affect healing dynamics by cell therapy. Such studies will be critical for examining how innate immune signaling at the level of macrophages and cardiomyocytes impacts the heart during an inflammatory injury response with the goal of modifying this response to benefit cardiac healing in patients.

抽象的 潜在动脉粥样硬化引起的心肌梗塞 (MI) 是主要疾病 在西方世界，这种后遗症会导致心力衰竭。我们有能力治疗这些 患者的心力衰竭进展并未超过轻度 20-30% 大约三十年前通过基于神经内分泌的管理实现了寿命[1]。 需要新的治疗途径，其中最引人注目的是直接 产生新的心肌细胞以再生心脏组织受损区域。 之前通过产生新的心肌细胞来再生心脏的尝试并没有成功。 尽管使用成体祖细胞进行了超过 18 年的研究，但仍取得了成功。 然而，在啮齿动物模型中对心脏祖细胞的研究确实表明了功能性 对心肌梗死损伤的心脏有益，尽管我们现在知道这并不是因为 显着的新肌细胞产生。相反，我们和其他人已经确定了一部小说 注射的祖细胞对细胞具有恢复活力的作用机制 通过改善免疫反应来治疗心肌梗死损伤的心脏。确实，我们已经展示了 细胞疗法注射到最近因缺血而受伤的心脏区域 再灌注（7 天后）可以优化愈合、减少梗塞面积扩大和 增强疤痕边界区的物理特性（Vagnozzi 等人，2020，《自然》）。这些 有益效果是通过选择性巨噬细胞亚型活性介导的 心脏，强调免疫反应对心血管健康的重要性 梗塞愈合和代偿。在这里，我们提出一个假设：选择性先天 免疫反应信号通路和巨噬细胞亚型极化可以 被用来帮助治愈心脏。我们更具体的假设是，治疗有一个 通过 Toll 样受体 (TLR) 信号传递的潜在保护成分 心肌细胞和巨噬细胞，这可以在治疗上利用来极化 免疫反应以获得更好的治愈效果。具体目标是： AIM #1，检查 通过 TLR 信号传递心脏先天免疫信号传导机制。目标#2，至 诱导改变心脏中的巨噬细胞亚型以重新编程先天免疫 细胞疗法的反应和愈合动力学。目标#3，确定成纤维细胞如何 与心肌梗死后受伤心脏中的巨噬细胞亚型沟通以影响愈合 细胞疗法的动力学。此类研究对于检查先天免疫如何发挥作用至关重要 巨噬细胞和心肌细胞水平的信号传导在心脏过程中会产生影响 炎症损伤反应，目的是改变这种反应以有益于心脏 患者康复。