COBRE: NE CREIGHTON U: P2: NEUROGULINS IN MYELIN REPAIR IN CNS & PNS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。目前还没有文献研究表皮生长因子超家族成员neuRegins及其信号分子(erb家族成员)在体内病毒诱导的病理反应中的作用，尽管已知它们在周围神经系统损伤后上调。这项建议中的研究将研究病毒引起的脊髓和坐骨神经髓鞘损伤后，中枢和周围神经系统(分别为CNS和PNS)的修复过程。因此，这一提议代表了一种研究这些蛋白质的新方法，而在任何特定目的上的成功都将极大地增强我们对三叉神经核和中枢神经系统的了解。在这一应用中，我们将检验这一假说，即神经调节蛋白通过通过erbB信号增强髓鞘形成过程来保护中枢神经系统和三叉神经核免受泰勒·S病毒诱导的病理影响。在这项应用中将解决以下特定目标：1)测试假设，即在TMEV介导的侮辱后，中枢和外周神经系统中NeuRegin上调。2)建立体外和体内模型，验证erb-B2信号增强中枢神经系统和三叉神经节髓鞘形成的假说。这一具体目标将利用三种方法：首先，我们将发展脊髓和坐骨神经的器官型培养，并在体外改变NeuRegins，以确定其对脱髓鞘的影响；其次，我们将培育靶向erb-B2条件性过表达小鼠，最后，我们将使用病毒载体将NeuRegin体内输送到病毒感染的小鼠。人类周围神经疾病既有遗传原因(如Charcot-Marie-Tooth病)，也有环境原因(如糖尿病)。在这种情况下可以观察到两种病理，轴索病或髓鞘病。每一个特定的目标都将使我们深入了解感染后维持/修复周围和中枢神经系统中的髓鞘的过程。我们的长期目标是探索干预脱髓鞘过程的可能性，并减轻与这些疾病相关的并发症。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. No body of literature examines the role of neuregulins, members of the epidermal growth factor superfamily, and their signaling molecules (erb family members) in response to in vivo virus-induced pathology, although they are known to be upregulated following injury to the peripheral nervous system. The studies in this proposal will examine the processes involved in the repair of the central and peripheral nervous systems (CNS, PNS respectively) following virus-induced damage to the myelin of the spinal cord and sciatic nerves. Thus, this proposal represents a novel approach to studying these proteins, and success in any of the specific aims would significantly enhance our knowledge of the PNS and CNS. In this application, we will test the hypothesis that neuregulins protect the CNS and PNS from Theiler¿s virus-induced pathology by enhancing myelination processes via erbB signaling. The following specific aims will be addressed in this application: 1) Test the hypothesis that neuregulin is upregulated in the central and peripheral nervous systems following TMEV-mediated insult. 2) Develop in vitro and in vivo models to test the hypothesis that increased erb-B2 signaling enhances myelination in the CNS and PNS. This specific aim will utilize 3 approaches: first, we will develop organotypic cultures of spinal cords and sciatic nerves and alter neuregulins in vitro to determine the effects on demyelination; second, we will develop targeted erb-B2 conditional over-expressing mice, and finally, we will use a viral vector to deliver neuregulin in vivo to virus infected mice. Peripheral neuropathies in humans have been attributed to both genetic (e.g. Charcot-Marie-Tooth disease) and environmental (e.g., diabetes) causes. Two pathologies can be observed in this condition, axonopathy or myelinopathy. Each of the specific aims will provide us with insights into the processes involved in maintaining / repairing myelin in the peripheral and central nervous systems following infection. Our long-term goal is to explore the possibilities of intervening in the demyelinating processes and alleviating the complications associated with these diseas