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

“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，神经学家和工程师合作开发了基于新兴科学微流体和微电穿孔的新技术，以解决神经系统和感官系统发育的基本问题。利用一种模式生物--微小的斑马鱼，人们正在研究新发现的免疫系统细胞因子在神经系统和感官系统(耳朵和眼睛)发育的早期阶段所起的作用。开发了一种斑马鱼微流控生物反应器，将发育中的胚胎神经系统或感觉系统的特定受限部分暴露在受控浓度的形态生物质(基本生长促进分子)流中。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原中，包括MIF(巨噬细胞移动抑制因子)，这是一种“炎症”细胞因子。细胞因子对免疫系统的发育至关重要，也是免疫系统形成后破坏性炎症反应的触发因素。首席研究员的实验室取得了令人惊讶的发现，免疫系统细胞因子，特别是MIF，对神经系统神经元(以及神经突起的发现)和眼睛和耳朵中的感觉细胞的最早发育也至关重要。MIF也可能在比引起炎症的浓度低一个数量级的情况下参与修复过程。因此，MIF和其他细胞因子在这些系统中扮演着神经营养因子或定向神经生长因子的角色，对于长期以来认为只有经典的(已经确定的)神经营养因子才能发挥这种作用的领域的科学家来说，这是一个令人惊讶的结果。微流控技术的使用以及分子的电穿孔直接进入发育中的斑马鱼内耳是这一新研究路线的关键。这个项目研究了MIF暴露于神经系统的受限部分和发育中的感觉系统促进其发育的作用机制，以及阻止它如何改变发育。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。斑马鱼的听觉系统发育在许多方面与人类耳朵的发育是相同的。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(他们开发了斑马鱼生物反应器)到博士后和教职员工，他们负责监督这项工作。

"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.