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

基本信息

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
项目类别：
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

项目摘要

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.

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。新的需要治疗途径，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 15 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，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精炼具有恢复活力的效果免疫反应。事实上，我们已经证明细胞疗法注射可以优化愈合、减少梗塞面积扩张并增强疤痕边界区的物理特性（Vagnozzi 等人，2020，《自然》）。这些有益的影响是通过心脏中选择性巨噬细胞亚型活动，强调了梗塞愈合和代偿中的免疫反应。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心肌梗死损伤。我们更具体的假设是 MI 损伤或细胞疗法通过 cGAS 具有潜在的保护成分刺痛心肌细胞和巨噬细胞，这可以治疗用于极化免疫反应以实现更好的愈合。具体目标是：目标#1，利用小鼠遗传学来识别心脏中的特定免疫细胞类型介导基于细胞疗法的心肌梗死损伤后心脏再生。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，至研究细胞疗法使心肌梗死后受伤的心脏恢复活力的机制。此类研究对于检查先天免疫信号如何在巨噬细胞在炎症损伤反应期间或由于细胞影响心脏治疗的目的是改变这种反应以利于患者的康复。