Lymphatic Support of Neurogenesis and Regeneration

项目摘要 淋巴管系统在体液平衡、清除细胞废物和免疫调节中起着关键作用。 应答最近的研究强调了它在再生反应过程中的整体贡献， 心脏损伤直到最近，中枢神经系统被认为是免疫特权的，缺乏免疫系统。 淋巴系统最近的研究表明，淋巴系统延伸到哺乳动物， 斑马鱼脑，但它在神经发生和对损伤的反应中所起的作用是未知的。需要 更好地了解如何减轻创伤性脑损伤（TBI）和中风的有害反应， 为了改善成果，促进再生势在必行。这项提案旨在揭示不同的 脑膜淋巴系统和脑内皮细胞的群体，并研究这些如何有助于成人 神经发生和再生。 以前，我们已经描述了斑马鱼心脏淋巴系统的发育， 确定了调节其规格和形成的信号通路。然后，我们证明， 成年斑马鱼心脏损伤后心脏淋巴管扩张。这项工作表明， 淋巴管对损伤作出反应，并通过运输免疫细胞来帮助再生反应。通过阻断 我们证明了淋巴管系统是促进再生所必需的， 防止心脏组织结疤。脑膜炎的发现使我们推测， 脑膜和脑组织是由不同的和不断变化的亚群组成的， 通过提供亲神经因子支持成年神经发生和损伤后的再生修复， 控制脑脊液（CSF）成分和免疫反应。 为了验证这一假设，我们将在斑马鱼中进行转录谱分析，作为成年斑马鱼的模型。 神经发生和脑再生。我们将描述不同群体的淋巴管内皮细胞 使用脑膜淋巴管内皮细胞的单细胞RNA测序分析及其对损伤的反应 以及来自未受伤和再生大脑的脑淋巴管内皮细胞。我们将开发工具， 单个淋巴系统组件的破坏，并测试这些对成人神经发生的影响。 这将为研究淋巴对哺乳动物神经发生的支持开辟新的途径 在健康和受伤后。为了进一步了解成人神经发生， 神经系统的反应和潜在的治疗，这是至关重要的是要了解如何淋巴 系统调节神经发生和再生的免疫和环境方面。

PROJECT SUMMARY The lymphatic vasculature plays a critical role in fluid homeostasis, removing cellular waste and immune responses. Recent research has highlighted its integral contribution during the regenerative response after cardiac injury. The central nervous system was until recently, believed to be immune privileged and lacking a lymphatic system. Recent studies have revealed the lymphatic system extends into the mammalian and zebrafish brain, however the role it plays in neurogenesis and the response to injury is unknown. The need to better understand how to alleviate the detrimental responses to Traumatic brain injury (TBI) and stroke and promote regeneration is imperative in order to improve outcomes. This proposal aims to uncover the different populations of meningeal lymphatic system and brain endothelial cells and study how these contribute to adult neurogenesis and regeneration. Previously, we have characterized the development of the zebrafish cardiac lymphatic system and identified the signaling pathways that regulate its specification and formation. We then demonstrated that the cardiac lymphatic vasculature expands post injury in the adult zebrafish heart. This work demonstrated that lymphatic vessels respond to injury and aid the regenerative response by trafficking immune cells. By blocking lymphangiogenesis we demonstrated that the lymphatic vasculature was required to promote regeneration and prevent scarring of heart tissue. The discovery of the meningeal lymphatics led us to hypothesize that meningeal and brain lymphatics are made up of different and changing sub-populations that uniquely support adult neurogenesis and regenerative repair after injury by providing neurotropic factors, controlling cerebral spinal fluid (CSF) composition and the immune response. To test this hypothesis, we will pursue transcriptional profiling in the zebrafish as a model of adult neurogenesis and brain regeneration. We will characterize the different populations of lymphatic endothelial cells and their response to injury using single-cell RNA sequencing analysis of meningeal lymphatic endothelial cells and brain lymphatic endothelial cells from uninjured and regenerating brains. We will generate tools to allow individual disruption of the lymphatic system components and test the impact of these on adult neurogenesis. Pursuit of this will open new avenues for investigation of lymphatic support of neurogenesis in mammalian systems in health and after injury. In order to further our comprehension of adult neurogenesis, the regenerative response of the nervous system and potential therapies for which it is critical to understand the how the lymphatic system modulates the immune and environmental aspects of neurogenesis and regeneration.