Elucidating the Mechanisms by which Macrophages and their TAM Receptors Promote Cardiac Regeneration

项目摘要 在美国，心肌梗死（MI）后心力衰竭的患病率正在增加，因为 目前的治疗策略不能使受损的心肌再生。虽然其他器官系统表现出 虽然成年人的心脏缺乏组织损伤后再生的能力，但却缺乏这种至关重要的能力。有了这些发现 多能细胞和先进的培养和分化技术，研究集中在干细胞- 基于治疗方法来补充耗尽的心肌细胞。然而，临床试验尚未注册 这些疗法对心脏功能的显著影响，因此需要新的和创造性的方法来 使受损的心肌再生。 值得注意的是，先天免疫细胞是心脏发育和再生所必需的。消融 新生儿心脏巨噬细胞（MΦs）损害再生反应，抑制肌肉化， 心肌的血管重建。然而，再生的精确分子机制， 巨噬细胞的重编程仍然未知。因此，本提案的长期目标是确定 新生巨噬细胞协调哺乳动物巨噬细胞的潜在细胞和分子机制 心脏再生 在影响MΦ功能的许多分子中，酪氨酸激酶的TAM（Tyro 3，Axl，MerTK）家族 受体正成为心脏病令人兴奋的治疗靶点。该提案假设， MerTK需要编程不同的新生儿心脏MΦ以分泌促再生介质， 协调心脏再生。这一假设将使用MerTK的遗传操作进行询问， 新生小鼠心肌梗死后。心脏的再生将取决于纤维化的程度， 诱导心肌细胞增殖和心脏功能恢复，如超声心动图所示。 此外，心脏损伤前后心脏MΦ的单细胞转录组学将揭示MerTK- 新生心脏MΦ利用依赖机制协调再生。心脏的这些机制 将验证新生MΦ的再生功能。 博士爱德华·索普的实验室和西北大学提供了专业知识、设施和必要的 彻底询问提案目的所需的设备。总体而言，拟议研究将 对先天免疫细胞及其受体如何直接执行再生功能的广泛影响。这些 这些发现可能会发现新的治疗策略，以诱导人类心脏再生，减轻心脏病的发生。 心肌梗死后心力衰竭对公共卫生的负担。

Project Summary The prevalence of post-myocardial infarction (MI) heart failure is increasing across the United States, since current therapeutic strategies fail to regenerate the injured myocardium. While other organ systems exhibit the ability to regenerate after tissue injury, the adult human heart lacks this crucial capability. With the discoveries of multipotent cells and advanced culturing and differentiation techniques, studies have focused on stem cell- based therapeutic approaches to replenish depleted cardiomyocytes. Clinical trials, however, have yet to register a significant impact of these therapies on cardiac function, thus necessitating novel and creative approaches to regenerate the injured myocardium. Remarkably, innate immune cells are required for both cardiac development and regeneration. Ablation of neonatal cardiac macrophages (MΦs) impairs the regenerative response, inhibiting the remuscularization and revascularization of the myocardium. The precise molecular mechanisms, however, for the regenerative reprogramming of macrophages remain unknown. Therefore, the long-term objective of this proposal is to identify the underlying cellular and molecular mechanisms by which neonatal macrophages coordinate mammalian cardiac regeneration. Among the many molecules that influence MΦ function, the TAM (Tyro3, Axl, MerTK) family of tyrosine kinase receptors are emerging as exciting therapeutic targets for heart disease. This proposal hypothesizes that MerTK is required to program distinct neonatal cardiac MΦs to secrete pro-regenerative mediators that coordinate cardiac regeneration. This hypothesis will be interrogated using genetic manipulation of MerTK in neonatal mice after myocardial infarction. Heart regeneration will be determined by the degree of fibrosis, the induction of cardiomyocyte proliferation, and the recovery of cardiac function as seen by echocardiography. Additionally, single-cell transcriptomics of cardiac MΦs before and after cardiac injury will unveil the MerTK- dependent mechanisms neonatal cardiac MΦs utilize to coordinate regeneration. These mechanisms of cardiac regeneration will be validated to confirm the regenerative functions of neonatal MΦs. Dr. Edward Thorp’s laboratory and Northwestern University provide both the expertise, facilities and necessary equipment required to thoroughly interrogate the aims of the proposal. Overall, the proposed study will have broad implications for how innate immune cells and their receptors directly execute regenerative functions. These findings may identify novel therapeutic strategies to induce cardiac regeneration in humans, alleviating the burden of post-MI heart failure on public health.