Endotelin-1 role in development and regeneration

Endotelin-1 在发育和再生中的作用

基本信息

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
项目类别：
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

项目摘要

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. !

新生儿慢性残疾的一个主要原因是弥漫性白质损伤（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、认知迟缓和神经行为异常。 DWMI 和髓鞘形成缺陷的细胞病理生理学是复杂且未完全理解。我们的实验室发表了大量关于新生儿脑损伤对婴儿的影响的文章白质发育，并证明 OL 祖细胞 (OPC) 延迟成熟为 OLs 会导致髓鞘形成异常、WM 功能改变和行为异常。在出生后和成人大脑中，OPC 源自室下区 (SVZ) 的放射状胶质细胞 (RGC)，大脑的主要胶质细胞和神经源性区域。 OPC 在 SVZ 中增殖并迁移到整个区域大脑转变为灰色和 WM，在那里它们成熟为有髓鞘的 OL。虽然一些重要的信号通路 OPC 增殖和成熟的稳态调节已被表征，但仍有许多未知之处在正常发育期间和受伤后的 SVZ 中。此外，尽管已确定内源性 OPC 对损伤的增殖反应对于扩大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 的扩散在很大程度上仍不明确。我们利用之前生成的内皮素-1 (ET-1) 和 ET-1 受体 (Ednr) 小鼠突变系，并且发现，在出生后的大脑中，RGC 衍生的 ET-1 发挥着一种新颖且不同的作用，即调节 OPC 增殖。在本提案中，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。我们将采用综合方法小鼠模型和大型哺乳动物（仔猪），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 中的作用正常发育过程中小鼠和仔猪的 OPC 增殖。其次，我们要确定ET-1的作用 HX 后 OPC 增殖和分化。最后，我们将定义 HX- 涉及的分子途径诱导 SVZ OPC 的改变，特别是位于 Ednr 激活下游并参与 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问题 HX 诱导 WM 成熟延迟的细胞机制，但也可能导致新的开发旨在减轻 HX 引起的新生儿大脑长期神经后遗症的治疗方法受伤。！