Roles of Primary Cilia in the Developing Cortex Exposed to Alcohol

初级纤毛在暴露于酒精的皮质发育中的作用

• 批准号: 9245104
• 负责人: KAZUE HASHIMOTO-TORII
• 金额: $ 20.78万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-10 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9245104
• 关键词: Actins; Acute; Alcohols; Alpha Cell; Animals; Behavior; Birth; Brain; Caspase; Cell Death; Cell Death Induction; Cells; Cerebral cortex; Cerebrum; Cilia; Cleaved cell; Data; Defense Mechanisms; Dendritic Spines; Detection; Development; Electrophysiology (science); Electroporation; Environment; Ethanol; FRAP1 gene; Fetal Alcohol Exposure; Folic Acid; Goals; Growth Factor Receptors; Human; Intervention; Knockout Mice; Label; Lead; Link; Mediating; Modeling; Molecular; Morphology; Mus; Neurites; Neurologic; Neurons; Organelles; Pathologic; Pathway interactions; Patients; Phenotype; Play; Role; Sensory; Signal Transduction; Structural defect; Testing; Time; Tubulin; Vertebral column; Work; alcohol exposure; alcohol intervention; alcohol response; base; effective intervention; endophenotype; environmental change; environmental stressor; experience; hippocampal pyramidal neuron; in utero; in vivo; molecular marker; mouse model; neuropsychiatry; postnatal; postsynaptic; prenatal; prevent

Project Summary/Abstract Prenatal alcohol exposure can lead to devastating effects on the developing cerebral cortex, thereby causing a wide spectrum of neurological and psychiatric conditions after birth. One of the promising intervention approaches lies in enhancing intrinsic protective mechanisms to overwhelm the triggered pathological mechanisms. Therefore, understanding the defense mechanisms deployed by neural cells is imperative for the development of potential therapies for alcohol-induced neuropsychiatric conditions. The goal of the proposed study is to characterize a new pathway by which primary cilia could suppress the adverse impact of alcohol on developing cortical neurons. The primary cilium is a unique organelle which is known to be essential for a cell to sense and respond to environmental changes. However, the role of cilia during brain development, particularly, in harsh prenatal environment such as exposure to alcohol or other environmental stressors remains largely unknown. By combining a mouse model of cilia deficiency specifically in the cerebral cortex and alcohol exposure during the brain sprout stage, we found evidences that support our hypothesis; cilia may play a critical role in protecting cortical neurons from alcohol-inducible dendritic/spine degeneration or/and other permanent morphological alterations. We will test this hypothesis by characterizing cortical phenotypes of cilia-deficient conditional knockout mice exposed to alcohol (Aim1), and testing candidate molecular mechanisms which may mediate cilia-dependent inhibition of dendritic/spine degeneration in vivo (Aim2).

项目总结/摘要 产前酒精暴露会对发育中的大脑皮层造成破坏性影响， 从而在出生后引起广泛的神经和精神疾病。之一 有希望的干预方法在于加强内在的保护机制， 压倒触发的病理机制。因此，理解辩护 神经细胞部署的机制对于开发潜在的治疗方法至关重要， 酒精引起的神经精神疾病拟议研究的目标是表征 初级纤毛可以抑制酒精对发育的不利影响的新途径 皮质神经元初级纤毛是一种独特的细胞器，已知其对于 细胞感知和响应环境变化。然而，纤毛在大脑中的作用 发育，特别是在恶劣的产前环境，如接触酒精或其他 环境压力因素在很大程度上仍然未知。通过将一个小鼠纤毛模型 大脑皮层的缺乏和大脑萌芽阶段的酒精暴露， 我们发现了支持我们假设的证据;纤毛可能在保护皮质方面发挥关键作用 来自酒精诱导的树突/棘变性或/和其他永久性神经元 形态改变我们将通过描述大脑皮层的表型来验证这一假设。 暴露于酒精的纤毛缺陷条件性敲除小鼠（Aim 1）和测试候选人 可能介导纤毛依赖性树突/棘抑制的分子机制 体内变性（Aim 2）。