Endotelin-1 role in development and regeneration

新生儿慢性残疾的一个主要原因是弥漫性白质损伤(DWMI)和髓鞘过少。更改后的 WM的发展与不良后果直接相关，包括脑瘫、认知延迟 和神经行为异常。弥漫性心肌梗死和髓鞘缺陷的细胞病理生理学基础是 很复杂，而且还没有完全理解。我们的实验室已经发表了大量关于新生儿脑损伤对 白质发育，并证明OL祖细胞(OPC)表现出延迟成熟为 OLS会导致异常的髓鞘形成，改变WM功能和行为异常。 在出生后和成人脑中，OPC起源于室下带(SVZ)的放射状胶质细胞(RGC)， 大脑中一个主要的神经胶质形成区和神经源区。OPC在SVZ中扩散，并在整个 脑到灰色和WM，在那里它们成熟为髓鞘OL。而一些重要的信号通路 已经确定了OPC增殖和成熟的动态平衡调节机制，但仍不清楚 在SVZ中，无论是在正常发育期间还是在受伤后。此外，虽然已经确定 内源性OPC对损伤的增殖反应对于扩大这一祖细胞库和 再生正常数量的OL，参与OPC调控的内源性分子信号 SVZ中的扩散在很大程度上仍然是未知的。 我们利用了我们之前产生的内皮素-1(ET-1)和ET-1受体(EDnR)小鼠突变株，以及 发现，在出生后的大脑中，RGC衍生的ET-1扮演着一个新的不同的角色，即调节OPC 扩散。在这个方案中，我们将检验这样一个假设，即RGC和OPC之间的ET-1信号起作用 在SVZ发育动态平衡和再生中起着至关重要的作用。我们将在以下方面使用综合方法 小鼠模型和较大的哺乳动物(小猪)，其中SVZ显示结构和细胞组成 与人脑一模一样。首先，我们将确定RGC来源的ET-1和特定的Ednr(S)在SVZ中的作用 OPC在小鼠和仔猪正常发育过程中的增殖。其次，我们将确定ET-1的作用 在HX后的OPC增殖和分化中。最后，我们将定义参与HX-的分子途径。 诱导SVZ OPC的改变，特别是在EdnR激活下游并参与 OPC增殖、细胞周期退出和细胞分化。总而言之，这些研究不仅将揭示关键的 HX诱导的WM成熟延迟的细胞机制，但也可能导致新的 减少HX所致新生儿脑内长期神经后遗症的治疗方法 受伤。 好了！

A major cause of chronic disability in neonates is diffuse white matter injury (DWMI) and hypomyelination. Altered development of the WM is directly associated with adverse outcomes, including cerebral palsy, cognitive delay and neurobehavioral abnormalities. The cellular pathophysiology underlying DWMI and defective myelination is complex and not fully understood. Our lab has extensively published on the effects of neonatal brain injury on white matter development, and demonstrated that OL progenitor cells (OPCs) display delayed maturation into OLs, which results in aberrant myelination, altered WM function and behavioral abnormalities. In the postnatal and adult brain, OPCs arise from radial glial cells (RGCs) of the subventricular zone (SVZ), a major gliogenic and neurogenic region of the brain. OPC proliferate in the SVZ and migrate throughout the brain to gray and WM, where they mature into myelinating OLs. While some important signaling pathways have been characterized, much remains unknown about homeostatic regulation of OPC proliferation and maturation in the SVZ, both during normal development and after injury. Furthermore, although it is established that the proliferative response of endogenous OPCs to injury is crucial for expanding this progenitor pool and for regenerating a normal number of OLs, the endogenous molecular signals involved in the regulation of OPC proliferation in the SVZ are still largely undefined. We utilized our previously generated Endothelin-1 (ET-1) and ET-1 receptor (Ednr) mouse mutant lines, and discovered that, in the postnatal brain, RGC-derived ET-1 plays a novel and different role, i.e. regulates OPC proliferation. In this proposal, we will test the hypothesis that ET-1 signaling between RGCs and OPCs plays a crucial role in SVZ developmental homeostasis and regeneration. We will use an integrated approach in a mouse model and in a larger mammal (piglet), in which the SVZ displays a structure and a cellular composition identical to the human brain. Firstly, we will define the role of RGC-derived ET-1 and specific Ednr(s) in SVZ OPC proliferation in mouse and piglet during normal development. Secondly, we will determine the role of ET-1 in OPC proliferation and differentiation after HX. Finally, we will define the molecular pathways involved in HX- induced alterations in SVZ OPCs, in particular genes that are downstream of Ednr activation and are involved in OPC proliferation, cell-cycle exit and cell differentiation. Together, these studies will not only shed light on crucial cellular mechanisms of HX-induced delay in WM maturation, but might also lead to the development of new therapeutic approaches aimed at lessening the long-term neurological sequelae of HX-induced neonatal brain injury. !