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Ethanol-induced disruption of kinase signaling pathways in brain development

乙醇诱导大脑发育中激酶信号通路的破坏

基本信息

批准号：
10706460
负责人：
ERIC Christopher OLSON
金额：
$ 36.68万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-19 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10706460
关键词：
Actins Acute Adaptor Signaling Protein Alcohols Axon Biochemical Biological Brain Cells Child Critical Pathways Cytoskeleton Defect Dendrites Development Disease Dissection Dose Elements Embryo Enzymes Ethanol Ethanol dependence Etiology Event Fetal Alcohol Exposure Fetal Alcohol Syndrome Future Genetic Genetic Predisposition to Disease Genetic study Goals Golgi Apparatus Growth In Vitro Intellectual functioning disability Knock-out Ligand Binding Ligands Live Birth Location Membrane Methodology Molecular Molecular Target Morphology Multipolar Neuron Mus Nervous System Neuronal Differentiation Neurons Phase Phosphorylation Phosphotransferases Positioning Attribute Protein Dephosphorylation Protein Tyrosine Kinase Proteins Receptor Protein-Tyrosine Kinases Reelin Signaling Pathway Research Personnel Role Signal Pathway Signal Transduction Site Structure Synaptic plasticity Syndrome Teratogenic effects Testing Tyrosine Phosphorylation United States alcohol consumption during pregnancy alcohol effect alcohol exposure alcohol research alcohol response axon growth axonal pathfinding cofilin fetal glycosylation in vivo maternal alcohol use migration mind control neuroprotection novel postnatal prevent receptor receptor binding response src-Family Kinases synaptic function white matter

项目摘要

ABSTRACT Fetal Alcohol Syndrome (FAS) is one of the leading causes of intellectual disability in the United States. The CDC estimates that 0.2-1.5 per 1000 live births are children with FASD, a syndrome characterized by disrupted fetal brain development and postnatal intellectual disability (ID). Disrupted connectivity including altered dendritic structure, axonal pathfinding and white matter tracts are common findings in FAS and are thought to be major contributors to ID. However, the cellular and biological targets of alcohol are diverse and it is not clear whether there are common underlying molecular mechanisms producing these disruptions. Identification of common molecular mechanism(s) would enable a deeper understanding of this disorder, inform studies of genetic susceptibilities and provide molecular targets for neuroprotective strategies. This proposal pursues our finding that acute ethanol (EtOH) exposure disrupts Src kinase activity in embryonic cortical neurons. Src is a critical non-receptor tyrosine kinase that sits at central positions in multiple signaling pathways including the Reelin-Dab1 signaling pathway which controls brain layer formation and dendritogenesis. We found that acute EtOH exposure activates Src and induces phosphorylation of many proteins including Dab1, an essential adaptor protein in the Reelin-signaling pathway. Remarkably, this dramatic increase in phosphorylation is followed by a sustained dephosphorylation response in which the phosphorylation of Reelin effectors including Dab1, Src itself and the actin severing protein n-cofilin return to baseline levels, or below. During the extended dephosphorylation phase, the Reelin-signaling pathway can no longer be activated by in vitro application of its ligand, Reelin. In AIM 1 of this proposal, we will determine whether Reelin-Dab1 silencing occurs in vivo after maternal dosing with EtOH. We will then determine whether genetic deficiency in Src prevents the phosphorylation and dephosphorylation responses. Genetically establishing the critical kinase that initiates the EtOH response in vivo will be essential for future neuroprotective efforts. We and others have shown that Reelin-Dab1 signaling controls Golgi-deployment in the forming dendrite. In AIM 2 we will examine whether Src activation and inactivation disrupts Golgi location and function. Disrupted Golgi function would be expected to impact membrane addition, glycosylation, secretion and appropriate expression of many proteins, with potential long term negative consequences on neuritogenesis and neuronal function. In AIM 3 we will determine whether the EphA3 signaling pathway is similarly disrupted by Src dysregulation. EphA3 is a receptor tyrosine kinase that is required for axonal and white matter tract development. We identified the activation site of EphA3 as a target of EtOH-induced Src dysregulation raising the possibility that EphA3 activation and then silencing may contribute to FASD-related white matter disruptions. Collectively, these studies will determine the contribution of EtOH-dependent Src dysregulation to altered developmental signaling in pathways critical for brain development.

摘要