Innate Immune Response in Cardiac Healing and Rejuvenation

心脏愈合和恢复活力中的先天免疫反应

• 批准号: 10625955
• 负责人: Jeffery D Molkentin
• 金额: $ 37.71万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-05 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625955
• 关键词: Acute; Adopted; Adult; Apoptosis; Area; Atherosclerosis; Bacteria; Basic Science; Bioinformatics; Biology; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Therapy; Cell secretion; Cells; Cicatrix; Clinical Data; Clinical Trials; Collaborations; Compensation; Complement Activation; DNA; Data; Dendritic Cells; Disease; Endothelial Cells; Event; Fibroblasts; Genes; Goals; Growth; Heart; Heart Injuries; Heart failure; Human; Immune; Immune response; Immune signaling; Infarction; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Injection of therapeutic agent; Injections; Injury; Innate Immune Response; Literature; Longevity; Macrophage; Mediating; Mus; Muscle Cells; Myocardial Infarction; Natural regeneration; Nature; Neurosecretory Systems; Outcome; Pathway interactions; Patients; Pattern recognition receptor; Production; Proteins; RNA; Regulation; Rejuvenation; Reporting; Reproducibility; Research; Rodent Model; Signal Pathway; Signal Transduction; Stimulator of Interferon Genes; Sting Injury; Structure; Therapeutic; Therapy trial; Tissue Expansion; Tissues; Toll-like receptors; Uncertainty; Virus; Western World; Work; adult stem cell; cardiac regeneration; cell type; fungus; genetic manipulation; healing; improved; injured; innate immune mechanisms; ischemic injury; mouse genetics; neutrophil; novel; novel therapeutics; paracrine; physical property; protective effect; repaired; response; response to injury; stem cell therapy; stem cells; transdifferentiation

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. 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 15 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, and we and others have identified a novel mechanism of benefit whereby injected progenitor cells had a rejuvenating effect through refinement of the immune response. Indeed, we have shown that cell therapy injections 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 infarct healing and compensation. Here we propose the hypothesis that selective innate immune response signaling pathways, and macrophage subtype polarization can be exploited to further heal MI injury. Our more specific hypothesis is that MI injury or cell therapy has an underlying protective component through cGAS- Sting 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 use mouse genetics to identify the specific immune cell-types in the heart that mediate cell therapy-based cardiac rejuvenation post-MI injury. AIM #2, To examine the mechanism of innate immune signaling in the heart through cGAS-Sting. AIM #3, To investigate the mechanisms whereby cell therapy rejuvenates the post-MI injured heart. Such studies will be critical for examining how innate immune signaling at the level of macrophages impacts the heart during an inflammatory injury response or due to cell therapy with the goal of modifying this response to benefit healing in patients.

摘要 由于动脉粥样硬化引起的心肌梗死（MI）是主要疾病 在西方世界导致心力衰竭的后遗症。我们治疗这些疾病的能力 患者和他们的心力衰竭没有进展超过轻度20-30%的扩展， 大约30年前通过基于神经内分泌的管理实现了寿命。新 需要治疗的途径，其中最引人注目的将是直接 产生新的心肌细胞以再生心脏组织的受损区域。 以前通过产生新的心肌细胞来再生心脏的尝试没有成功。 尽管使用成人祖细胞进行了超过15年的研究，但仍然取得了成功。 然而，在啮齿动物模型中对心脏祖细胞的研究确实显示了功能性的 有益于MI损伤的心脏，我们和其他人已经确定了一种新的机制， 注射的祖细胞通过改善 免疫反应。事实上，我们已经证明，细胞治疗注射可以优化 愈合，减少梗死面积扩大和增加疤痕边缘区物理性质 （Vageli等人，2020，Nature）。这些有益的影响是通过 选择性巨噬细胞亚型的活动在心脏，强调的重要性， 梗死愈合和补偿中免疫应答。这里我们提出假设 选择性先天免疫反应信号通路和巨噬细胞亚型 极化可用于进一步治愈MI损伤。我们更具体的假设是 心肌梗死损伤或细胞疗法通过cGAS具有潜在的保护成分， 在心肌细胞和巨噬细胞中都有刺痛， 利用它来抑制免疫反应以获得更好的愈合。具体目标是： 目的#1，利用小鼠遗传学来鉴定心脏中的特异性免疫细胞类型 介导MI损伤后基于细胞治疗的心脏再生。目标#2，检查 通过cGAS-Sting的心脏先天免疫信号传导机制。目标#3，目标 研究细胞疗法使心肌梗死后受损心脏恢复活力的机制。 这些研究对于研究先天免疫信号如何在免疫水平上发挥作用至关重要。 巨噬细胞在炎性损伤反应期间或由于细胞 治疗的目的是改变这种反应，以利于患者的愈合。