Immune Response-Mediated Regulation of Cardiomyocyte Growth and Renewal

免疫反应介导的心肌细胞生长和更新调节

• 批准号: 10625948
• 负责人: Hesham Sadek
• 金额: $ 216.21万
• 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/10625948
• 关键词: Adult; Aging; Area; Biological Process; Cardiac; Cardiac Myocytes; Cell Cycle Arrest; Cell Cycle Regulation; Cell Therapy; Cells; Cessation of life; Chronic Disease; Complex; Dedications; Failure; Functional disorder; Generations; Goals; Growth; Heart; Heart Hypertrophy; Heart failure; Hyperplasia; Hypertrophy; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunologics; Immunology; Inflammatory; Injections; Injury; Innate Immune Response; Investigation; Lead; Life; Link; Macrophage; Mediating; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Neonatal; Pathologic; Pathology; Pathway interactions; Pattern; Physiological; Physiology; Play; Process; Proliferating; Regulation; Reporting; Research Personnel; Role; Signal Transduction; Sterility; Stimulator of Interferon Genes; Testing; Therapeutic; Time; Ventricular Remodeling; Work; cardiac regeneration; frontier; healing; immune activation; interest; member; multidisciplinary; postnatal; postnatal development; prevent; programs; repaired; response; response to injury; single-cell RNA sequencing

Heart failure progression is a complex biological process that is precipitated by the maladaptive myocardial response to injury, compounded by failure of the adult heart to replace lost or damaged cardiomyocytes. Conceivably, identifying common pathways that regulate these two seemingly unrelated processes would profoundly impact therapeutic strategies to prevent, and even reverse heart failure progression. Numerous observations by members of the proposed consortium and others support the notion that the endogenous capacity of the neonatal mammalian heart to proliferate fades in the early postnatal life as a switch from hyperplastic to hypertrophic growth of cardiomyocytes takes place. Members of the proposed consortium and others have also previously demonstrated that mechanisms linked to activation of immune response may play a role in cardiomyocyte hypertrophy, death, healing and even stimulation of new cardiomyocyte generation. The current proposal brings together several groups with significant expertise in immunology, myocardial remodeling, hypertrophy and regeneration with the overall goal of determining the role of immune response signaling in regulation of cardiac growth, healing and regeneration. Indeed, the immune response has taken center stage in the past several years as a primary determinant of both healthy cardiac aging and healing after injury, as well as a determinant of chronic disease states when it is inappropriately regulated. Thus, this Program Project will investigate a frontier and emerging area of scientific investigation involving the intersection between the immune system and the myocardium. Specifically, studies will examine the role of innate immune response signals in cardiomyocyte cell cycle regulation, as well as in myocardial remodeling and hypertrophy. In addition, dedicated studies will examine the role of cGAS-STING expression in cardiomyocytes and in immune cells in regulation of cardiac growth and regeneration. Finally, studies in the proposed Program Project will examine the role of macrophage subtypes in mediating myocardial response to cell therapy as well as injury. The proposed Program Project is well in line with the interest and expertise of the groups in the network and extends their focus into a highly relevant and poorly explored area of cardiac pathophysiology. The current proposal creates a new shared focus for all the groups in the Program Project that aims to establish a new paradigm in the field.

心力衰竭进展是一个复杂的生物学过程， 对损伤的反应，由于成年心脏无法取代丢失或受损的心肌细胞而加剧。 可以想象，确定调节这两个看似无关的过程的共同途径， 深刻影响预防甚至逆转心力衰竭进展的治疗策略。许多 拟议的合作体成员和其他人的意见支持这样一种观点， 新生哺乳动物心脏的增殖能力在出生后的早期逐渐减弱， 发生心肌细胞的增生到肥大生长。拟议联合体的成员和 其他人先前也证明了与免疫应答激活相关的机制可能起作用， 在心肌细胞肥大、死亡、愈合甚至刺激新心肌细胞产生中起作用。的 目前的提议汇集了几个在免疫学、心肌保护、 重塑，肥大和再生的总体目标是确定免疫反应的作用 在调节心脏生长、愈合和再生中的信号传导。事实上，免疫反应已经 在过去的几年中，作为健康心脏衰老和术后愈合的主要决定因素， 损伤，以及慢性疾病状态的决定因素，当它被不适当地调节。因此，这 计划项目将调查涉及交叉的科学调查的前沿和新兴领域 免疫系统和心肌之间的联系具体来说，研究将检查先天免疫的作用， 在心肌细胞周期调节以及心肌重塑和肥大中的反应信号。 此外，专门的研究将检查cGAS-STING表达在心肌细胞中的作用， 免疫细胞调节心脏生长和再生。最后，研究了拟议的方案项目 将研究巨噬细胞亚型在介导心肌对细胞治疗的反应以及损伤中的作用。 拟议的计划项目完全符合网络中各团体的兴趣和专业知识， 将他们的注意力扩展到心脏病理生理学的高度相关和探索不足的领域。当前 提案为计划项目中的所有团体创建了一个新的共同焦点，旨在建立一个新的 领域的典范。