Endotelin-1 role in development and regeneration

Endotelin-1 在发育和再生中的作用

• 批准号: 10246490
• 负责人: Vittorio Gallo
• 金额: $ 61.52万
• 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/10246490
• 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; Stem Cell Development; 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质损伤（DWMI）和低切术。改变 WM的发展与不良结果直接相关，包括脑瘫，认知延迟 和神经行为异常。 DWMI和缺陷髓鞘的细胞病理生理学是 复杂且不完全理解。我们的实验室广泛发表了关于新生儿脑损伤对 白质开发，并证明OL祖细胞（OPC）显示出延迟成熟到 OLS导致异常的髓鞘形成，改变了WM功能和行为异常。 在产后和成年大脑中，OPC来自室室下区（SVZ）的径向神经胶质细胞（RGC）， 大脑的主要神经胶质和神经源区域。 OPC在SVZ中扩散并在整个过程中迁移 大脑到灰色和WM，在那里它们成熟到髓生成的OL中。虽然一些重要的信号通路有 被表征了，关于OPC增殖和成熟的稳态调节，许多未知 在SVZ中，在正常发育和受伤后。此外，尽管已经确定 内源性OPC对损伤的增生反应对于扩大该祖细胞池和对 再生正常数量的OL，涉及OPC调节的内源分子信号 SVZ中的扩散仍然很大不确定。 我们利用了先前生成的内皮素-1（ET-1）和ET-1受体（EDNR）小鼠突变型系，以及 发现，在产后大脑中，RGC衍生的ET-1扮演着一种新颖和不同的作用，即调节OPC 增殖。在此提案中，我们将测试RGC和OPC之间的ET-1信号传导的假设 在SVZ发育稳态和再生中起着至关重要的作用。我们将在 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 与人脑相同。首先，我们将定义RGC衍生的ET-1和特定EDNR在SVZ中的作用 在正常发育过程中，小鼠和小猪中的OPC增殖。其次，我们将确定ET-1的作用 在HX之后的OPC增殖和分化中。最后，我们将定义涉及HX-的分子途径 SVZ OPC的诱导改变，特别是EDNR激活下游并参与的基因 OPC增殖，细胞周期出口和细胞分化。这些研究不仅会阐明至关重要 HX引起的WM成熟延迟的细胞机制，但也可能导致新的发展 治疗方法旨在减少HX诱导的新生儿大脑的长期神经后遗症 受伤。 呢