Innate immune response signaling in cardiac injury healing

心脏损伤愈合中的先天免疫反应信号

基本信息

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
项目类别：
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

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 [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.

抽象的基本动脉粥样硬化引起的心肌梗塞（MI）是主要疾病续集引起了西方世界的心力衰竭。我们对待这些的能力患者和心力衰竭的进展尚未超过20-30％的延伸大约三十年前，通过基于神经内分泌的管理[1]实现了生命跨度。需要新的治疗途径，其中最戏剧性的是直接产生新的心肌细胞以再生心脏组织受损区域。以前通过新的肌细胞生产来再生心脏的尝试尚未尽管使用成人祖细胞进行了超过18年的研究，但仍取得了成功。但是，在啮齿动物模型中对心脏祖细胞的研究确实显示了功能有益于伤害的心脏，尽管我们现在知道这不是由于重大的新肌细胞产生。相反，我们和其他人确定了一本小说受益机制，注射祖细胞对祖细胞具有振兴作用通过细化免疫反应，心脏损害的心脏。确实，我们已经表明那种细胞疗法的注射侧面是近期局部受伤的心脏损伤区域的缺血区域再灌注（7天后）可以优化愈合，减少梗塞区域的扩张和增强疤痕边框物理特性（Vagnozzi等，2020，自然）。这些通过选择性巨噬细胞亚型活性介导了有益作用心脏，强调免疫反应在心血管健康中的重要性梗塞愈合和补偿。在这里，我们提出了选择性先天的假设免疫反应信号通路和巨噬细胞亚型极化可以是被利用以帮助治愈心脏。我们更具体的假设是治疗有通过Toll样受体（TLR）信号传导的潜在保护分量心肌细胞和巨噬细胞，这可以在治疗上利用以极化免疫反应以更好地康复。具体目的是：目标1，检查通过TLR信号传导，先天免疫信号传导的机理。目标＃2，to 在心脏中诱导的巨噬细胞亚型以重新编程先天免疫通过细胞疗法的反应和愈合动力。目标＃3，以确定成纤维细胞的方式与巨噬细胞的亚型交流，以影响治愈的心脏受伤的心脏细胞疗法动力学。此类研究对于研究天生的免疫力至关重要巨噬细胞和心肌细胞水平的信号传导会影响心脏炎症损伤反应，目的是修改这种反应以使心脏受益患者的愈合。