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。本提案旨在揭示 脑膜淋巴系统在成人神经发生和再生中的作用及其机制 有助于在体内平衡和损伤反应期间产生新的神经元。 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， 脑膜再生支持成年神经发生和损伤后的再生修复， 神经营养因子，控制脑脊液（CSF）的组成和免疫反应。 为了验证这一假设，我们将在斑马鱼作为成年神经发生的模型中追求两个目标， 大脑再生目标1将使用时间推移成像表征淋巴对损伤的反应， 确定淋巴系统的破坏如何影响成人神经发生。使用质谱分析，我们 将分析脑脊液的成分，以确定支持神经发生的淋巴管分泌因子。在目标2 我们将操纵脑膜淋巴管系统的发育，并使用转录组学分析， 确定对免疫细胞群体和反应的影响。 这些假说的研究将为淋巴支持神经发生的研究开辟新的途径 在健康和受伤后的哺乳动物系统中。为了加深我们对成人神经发生的理解， 神经系统的再生反应和潜在的治疗方法，关键是要了解 淋巴系统如何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 role of the meningeal lymphatic system in adult neurogenesis and regeneration and the mechanisms through which it contributes to generating new neurons during homeostasis and injury response. 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 lymphatics 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 two aims in the zebrafish as a model of adult neurogenesis and brain regeneration. Aim 1 will characterize the lymphatic response to injury using time lapse imaging and determine how disruption of the lymphatic system impacts adult neurogenesis. Using mass spectrometry, we will analyze the composition of the CSF to identify lymphangiocrine factors that support neurogenesis. In Aim 2 we will manipulate the development of the meningeal lymphatic vasculature and use transcriptomic analyses to determine the impact on immune cell populations and response. Pursuit of these hypotheses 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 forward it is critical to understand the how the lymphatic system modulates the immune and environmental aspects of neurogenesis and regeneration.