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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：
10665603
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/10665603
关键词：
Ablation 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 Learning Disabilities Mammals Molecular Motor Mus Mutant Strains Mice Myelin Natural regeneration Neonatal Neonatal Brain Injury Neuroglia Neurologic Nuclear Oligodendroglia Pathway interactions Perinatal Play Predisposition Publishing Radial Receptor Activation 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 migration mouse model myelination neonate neurobehavioral novel novel therapeutic intervention oligodendrocyte progenitor pharmacologic postnatal prevent progenitor programs receptor expression 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）和髓鞘退化。改变