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

项目摘要 在美国，心肌梗死后心力衰竭(MI)的患病率正在上升，因为 目前的治疗策略不能使受损的心肌再生。而其他器官系统则表现出 在组织损伤后再生的能力，成人心脏缺乏这一关键能力。有了这些发现 多潜能细胞和先进的培养和分化技术，研究集中在干细胞- 补充耗尽的心肌细胞的基础治疗方法。然而，临床试验还没有注册。 这些疗法对心脏功能的重大影响，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，心脏发育和再生都需要先天免疫细胞。烧蚀 新生儿心肌巨噬细胞(MΦS)损伤再生反应，抑制再肌化和 心肌血运重建。然而，再生的精确分子机制 巨噬细胞的重新编程仍然未知。因此，这项提议的长期目标是确定 新生儿巨噬细胞协调哺乳动物的潜在细胞和分子机制 心脏再生。 在影响MΦ功能的众多分子中，(Tyro3，Ax1，MerTK)家族是酪氨酸激酶 受体正在成为心脏病的令人兴奋的治疗靶点。这项提议假定 MerTK需要对不同的新生儿心肌MΦS进行编程，以分泌促再生介质 协调心脏再生。这一假说将通过对MerTK的遗传操作在 新生小鼠心肌梗死后。心脏再生将由纤维化的程度决定， 诱导心肌细胞增殖，并恢复心脏功能，如超声心动图所见。 此外，心脏损伤前后MΦS的单细胞转录将揭示MerTK- 新生儿心肌MΦS用于协调再生的依赖机制心脏的这些机制 将对再生进行验证，以确认新生儿MΦS的再生功能。 爱德华·索普博士的实验室和西北大学提供了专业知识、设施和必要的 彻底审问提案目标所需的设备。总体而言，拟议的研究将具有 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 研究结果可能会确定新的治疗策略，以诱导人类心脏再生，缓解 心肌梗死后心力衰竭对公众健康的负担。

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.