Endotelin-1 role in development and regeneration

Endotelin-1 在发育和再生中的作用

• 批准号: 10027098
• 负责人: Vittorio Gallo
• 金额: $ 59.74万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10027098
• 关键词: Adult; Affect; Anatomy; Animal Model; Astrocytes; Behavioral; Brain; Brain Injuries; Brain region; Cell Cycle; Cell Differentiation process; Cell Maturation; Cell physiology; Cells; Cerebral Palsy; Chronic; Cognitive; Complex; Corpus Callosum; Data; Defect; Demyelinations; Development; Diffuse; Doctor of Philosophy; Endothelin A Receptor; Endothelin-1; Functional disorder; Future; Gene Expression; Genes; Genetic; Homeostasis; Human; Injury; Knowledge; Lead; Learning Disabilities; Light; Mammals; Molecular; Motor; Mus; Mutant Strains Mice; Myelin; Natural regeneration; Neonatal; Neonatal Brain Injury; Neuroglia; Neurologic; Nuclear; Oligodendroglia; Pathway interactions; Perinatal; Pharmacology; Play; Proliferating; Publishing; Radial; Recovery; Regulation; Regulatory Pathway; Role; Signal Pathway; Signal Transduction; Slice; Structure; Testing; Therapeutic Intervention; Transgenic Mice; Up-Regulation; Work; adverse outcome; cellular development; disability; genetic manipulation; insight; mouse model; myelination; neonate; neurobehavioral; novel; novel therapeutic intervention; oligodendrocyte progenitor; postnatal; prevent; progenitor; programs; response; response to injury; stem cell proliferation; stem cells; subventricular zone; white matter; white matter injury

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. !

新生儿慢性残疾的主要原因是弥漫性白色物质损伤（DWMI）和髓鞘形成不足。改变 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DWMI和髓鞘形成缺陷的细胞病理生理学基础是 很复杂，没有完全理解。我们的实验室已经广泛发表了关于新生儿脑损伤对 白色物质的发展，并证明OL祖细胞（OPCs）显示延迟成熟， OLs导致髓鞘形成异常、WM功能改变和行为异常。 在出生后和成年脑中，OPCs来自室管膜下区（SVZ）的放射状胶质细胞（RGC）， 大脑中主要的胶质和神经生成区域。OPC在SVZ中增殖并在整个SVZ中迁移。 脑灰质和WM，在那里它们成熟为髓鞘形成的OL。虽然一些重要的信号通路 尽管已经被鉴定，但关于OPC增殖和成熟的稳态调节仍有许多未知之处 在SVZ中，无论是在正常发育期间还是在损伤后。此外，虽然已经确定， 内源性OPCs对损伤的增殖反应对于扩大这种祖细胞库和 再生正常数量的OL，参与OPC调节的内源性分子信号 SVZ中的增殖在很大程度上仍然不确定。 我们利用我们先前产生的内皮素-1（ET-1）和ET-1受体（Ednr）小鼠突变株， 发现，在出生后的大脑中，RGC衍生的ET-1发挥着新的和不同的作用，即调节OPC 增殖在本研究中，我们将检验RGCs和OPCs之间的ET-1信号通路在视网膜神经节细胞中起作用的假说。 在SVZ发育稳态和再生中起关键作用。我们将采用综合方法， 小鼠模型和较大哺乳动物（仔猪）中，其中SVZ显示结构和细胞组成 与人类大脑相同。首先，我们将明确RGC衍生的ET-1和特异性Ednr在SVZ中的作用， 正常发育过程中小鼠和仔猪的OPC增殖。其次，我们将确定ET-1的作用 HX后OPC增殖和分化。最后，我们将定义涉及HX的分子途径- 诱导SVZ OPCs的改变，特别是Ednr激活下游的基因， OPC增殖、细胞周期退出和细胞分化。总之，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 旨在减轻HX诱导的新生儿脑的长期神经学后遗症的治疗方法 损伤 !