Lymphatic support of neurogenesis and regeneration

神经发生和再生的淋巴支持

• 批准号: 10556837
• 负责人: Michael Harrison
• 金额: $ 45.18万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556837
• 关键词: Ablation; Acute; Address; Adult; American; Animals; Behavior; Biology; Brain; Brain Injuries; Cardiac; Cells; Central Nervous System; Cerebrospinal Fluid; Child; Cicatrix; Clinical; Clinical Trials; Cognition; Collaborations; Comprehension; Development; Fluid Balance; Genetic; Goals; Health; Heart; Heart Injuries; Homeostasis; Human; Image; Imaging Techniques; Immune; Immune response; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injury; Investigation; Knowledge; Lead; Leucocytic infiltrate; Lymphangiogenesis; Lymphatic; Lymphatic System; Lymphocyte; Mammals; Mass Spectrum Analysis; Mediating; Meningeal lymphatic system; Modeling; Molecular; Natural regeneration; Nerve Regeneration; Nervous System; Neurons; Outcome; Pathway interactions; Patient-Focused Outcomes; Pharmaceutical Preparations; Physical therapy; Play; Population; Positioning Attribute; Publishing; Regenerative response; Rehabilitation therapy; Research; Role; Signal Pathway; Signal Transduction; Skin; Skin Tissue; Specific qualifier value; Speech; Stroke; Symptoms; System; Systems Development; TBI Patients; TBI treatment; Techniques; Testing; Tissue Model; Tissues; Transgenic Organisms; Traumatic Brain Injury; Traumatic injury; United States; Vascular Endothelial Growth Factor C; Vertebrates; Vision; Visualization; Work; Zebrafish; adult neurogenesis; body system; brain dysfunction; cardiac regeneration; cell behavior; cell motility; chemokine; defined contribution; disability; healing; immunoregulation; improved; improved outcome; in vivo; inflammatory modulation; insight; lymphatic development; lymphatic vasculature; lymphatic vessel; neurogenesis; neuron regeneration; neurotropic; new technology; novel; prevent; programs; regenerative; regenerative repair; repaired; response; response to brain injury; response to injury; time use; tissue regeneration; tissue repair; tool; trafficking; transcriptomics; wasting; young adult; zebrafish development

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.

项目概要 淋巴管系统在液体稳态、清除细胞废物和免疫方面发挥着关键作用 回应。最近的研究强调了它在术后再生反应中的不可或缺的贡献 心脏损伤。直到最近，中枢神经系统还被认为具有免疫特权，并且缺乏免疫系统。 淋巴系统。最近的研究表明，淋巴系统延伸到哺乳动物和 斑马鱼大脑，但它在神经发生和损伤反应中所起的作用尚不清楚。需要 更好地了解如何减轻对创伤性脑损伤 (TBI) 和中风的有害反应 为了改善结果，促进再生势在必行。该提案旨在揭示 脑膜淋巴系统在成人神经发生和再生中的作用及其机制 有助于在稳态和损伤反应期间产生新的神经元。 之前，我们已经描述了斑马鱼心脏淋巴系统的发育和 确定了调节其规范和形成的信号通路。然后我们证明了 成年斑马鱼心脏受伤后心脏淋巴管系统扩张。这项工作表明 淋巴管对损伤做出反应，并通过运输免疫细胞来帮助再生反应。通过阻止 淋巴管生成 我们证明淋巴管系统是促进再生和促进淋巴管生成所必需的 防止心脏组织留下疤痕。脑膜淋巴管的发现使我们推测 脑膜淋巴管通过提供支持成人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）成分和免疫反应。 为了检验这一假设，我们将在斑马鱼中追求两个目标作为成年神经发生的模型和 大脑再生。目标 1 将使用延时成像来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。使用质谱分析法，我们 将分析脑脊液的组成，以确定支持神经发生的淋巴管分泌因子。目标 2 我们将操纵脑膜淋巴管系统的发育并使用转录组分析来 确定对免疫细胞群和反应的影响。 对这些假设的追求将为研究神经发生的淋巴支持开辟新途径 在健康和受伤后的哺乳动物系统中。为了进一步理解成人神经发生， 神经系统的再生反应和潜在的治疗方法，了解神经系统的再生反应和潜在的治疗方法至关重要 淋巴系统如何调节神经发生和再生的免疫和环境方面。