Role of the cytokine macrophage migration inhibitory factor (MIF) as a neurotrophin in Zebrafish neurogenesis

细胞因子巨噬细胞迁移抑制因子（MIF）作为神经营养素在斑马鱼神经发生中的作用

• 批准号: 0930096
• 负责人: Kate Barald
• 金额: $ 40万
• 依托单位: Regents of the University of Michigan - Ann Arbor
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0930096&HistoricalAwards=false
• 关键词: Role; cytokine; macrophage; migration; inhibitory

"This award is funded under the American Recovery and Reinvestment Act of 2009(Public Law 111-5)."In this project new technologies based on the emerging sciences of microfluidics and microelectro-poration have been developed in a partnership between neuroscientists and engineers to address fundamental questions of nervous system and sensory system development. Using a model organism, the tiny zebrafish, newly recognized factors "immune system cytokines" are being studied for their roles in the earliest stages of development of the nervous system and sensory systems (ear and eye). A zebrafish microfluidic bioreactor was developed to expose specific circumscribed parts of the growing embryo's nervous system or sensory systems to streams of morphogens (fundamental growth promoting molecules), in controlled concentrations. In the bioreactor, small areas of the developing nervous system, the ear or the eye can be bathed in such morphogens, including MIF (macrophage migration inhibitory factor), which is an "inflammatory" cytokine. Cytokines are vital for immune system development as well as triggers of damaging inflammatory reactions after the immune system forms. The primary investigator's laboratory has made the surprising discovery that immune system cytokines, and especially MIF, are also vital for the very earliest development of nervous system neurons (and pathfinding of neurites) and sensory cells in the eye and ear. MIF could also be involved in repair processes at concentrations orders of magnitude below those that cause inflammation. MIF and other cytokines therefore act as "neurotrophins" or directional nerve growth factors in these systems, a surprising outcome to scientists in a field that had long thought only classical (already identified) neurotrophins could play such a role. The use of microfluidic technologies as well as electroporation of molecules directly into the developing zebrafish inner ear were key to this new line of research. This project investigates the mechanism of action by which MIF exposure to circumscribed parts of the nervous system and developing sensory systems promotes their development and how blocking it alters development. Fundamental links between the developing nervous and sensory systems and the immune system can be studied in this model. Zebrafish auditory system development is, in many ways, the same as that in the human ear. The same molecules that are active in zebrafish are active in humans, but zebrafish are easier to study. Development takes place outside the mother and is extremely rapid (a scale of hours to a few days rather than weeks or months). This project will provide training opportunities for interdisciplinary teams of neuroscientists and engineers at all levels from undergraduate and graduate students (who developed the zebrafish bioreactor) to the postdoctoral and faculty level, who supervised the work.

“该奖项是根据2009年美国复苏和再投资法案（公法111-5）资助的。“在这个项目中，神经科学家和工程师合作开发了基于微流体和微电穿孔新兴科学的新技术，以解决神经系统和感觉系统发育的基本问题。 使用模式生物，微小的斑马鱼，新认识的因素“免疫系统细胞因子”正在研究其在神经系统和感觉系统（耳朵和眼睛）发育的最早阶段的作用。 斑马鱼微流控生物反应器的开发是为了将生长中的胚胎的神经系统或感觉系统的特定限制部分暴露于受控浓度的形态发生剂（基本生长促进分子）流。 在生物反应器中，发育中的神经系统、耳朵或眼睛的小区域可以沐浴在这样的形态因子中，包括MIF（巨噬细胞迁移抑制因子），这是一种“炎性”细胞因子。 细胞因子对免疫系统发育至关重要，也是免疫系统形成后破坏性炎症反应的触发因素。 主要研究者的实验室已经做出了令人惊讶的发现，免疫系统细胞因子，特别是MIF，对于神经系统神经元（和神经突的寻路）和眼睛和耳朵中的感觉细胞的最早发育也是至关重要的。 MIF也可能参与修复过程，其浓度低于引起炎症的浓度。 因此，MIF和其他细胞因子在这些系统中充当“神经营养因子”或定向神经生长因子，这对长期以来认为只有经典（已经确定）神经营养因子才能发挥这种作用的科学家来说是一个令人惊讶的结果。 微流控技术的使用以及将分子直接电穿孔到发育中的斑马鱼内耳是这一新研究路线的关键。 该项目研究了MIF暴露于神经系统和发育中的感觉系统的限定部分促进其发育的作用机制，以及阻断它如何改变发育。 在这个模型中可以研究发育中的神经和感觉系统与免疫系统之间的基本联系。 斑马鱼听觉系统的发育在许多方面与人类耳朵的发育相同。 在斑马鱼中活跃的分子在人类中也是活跃的，但斑马鱼更容易研究。 发育发生在母亲之外，而且非常迅速（从几小时到几天，而不是几周或几个月）。 该项目将为各级神经科学家和工程师的跨学科团队提供培训机会，从本科生和研究生（开发斑马鱼生物反应器）到博士后和教师级别，监督工作。