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Immune molecules in early postnatal nervous system development

出生后早期神经系统发育中的免疫分子

基本信息

批准号：
7777203
负责人：
A Kimberley McAllister
金额：
$ 33.22万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-15 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7777203
关键词：
Address Adult Age Autistic Disorder Binding Biochemistry Biological Assay Brain Cells Development Disease Electron Microscopy Family Glutamates Goals Histocytochemistry Human Image Immune Immune response Immune system Immunoelectron Microscopy Immunoglobulins Immunohistochemistry Immunologic Receptors In Vitro KLRA1 gene Knock-out Knockout Mice Label Location Major Histocompatibility Complex Measures Mediating Mediator of activation protein Molecular Natural Killer Cells Nervous system structure Neuraxis Neurodevelopmental Disorder Neurons Pathogenesis Play Proteins RNA Interference Receptor Signaling Role Schizophrenia Slice Staging Stimulus Synapses Testing Time Tissues Transfection base critical period density immune function immunocytochemistry in vivo killer inhibitory receptor nervous system development novel overexpression patch clamp postnatal postsynaptic presynaptic public health relevance receptor synaptic function synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): Although there has been evidence for cross-talk between the immune and nervous systems for years, the idea that immune molecules have non-immune functions in the normal developing nervous system has only recently gained credence. This idea is based on observations that the primary mediators of the adaptive immune response, major histocompatibility complex class I (MHCI) molecules, are expressed in the brain where they mediate activity-dependent refinement of connections. MHCI molecules are also attractive candidates for molecular mediators of the effects of an abnormal or strong immune response on the developing brain, which has been implicated in the pathogenesis of several neurodevelopmental disorders, including autism and schizophrenia. The central goal of this proposal is to determine the function of MHCI during the initial establishment of cortical connections, a comparable developmental stage to the time of the immune challenge that may predispose humans toward neurodevelopmental disorders. Using immunocyto- and histochemistry, electron microscopy, cell and slice culture and transfection, a novel long-term imaging assay, and whole-cell patch-clamp recording, we will address the following Aims. (1) To determine the localization of MHCI molecules in vivo and in vitro during cortical development. (2) To test the hypothesis that MHCI molecules regulate the initial establishment and function of cortical connections in vivo and in vitro. (3) To determine whether MHCI molecules negatively regulate the establishment of cortical connections by inhibiting synapse formation, increasing synapse elimination, or both. (4) To test the hypothesis that MHCI molecules act through natural killer cell receptors to negatively regulate the establishment of cortical connections. Results from this proposal should reveal novel functions of MHCI in the typically developing brain, as well as potential mechanisms for how they might contribute to neurodevelopmental disorders. PUBLIC HEALTH RELEVANCE: Although a wide range of environmental stimuli have been proposed to play a role in the pathogenesis of neurodevelopmental disorders including autism and schizophrenia, many of these stimuli have in common the ability to alter immune function. Since MHCI molecules initiate and mediate the immune response 9 and are present in the brain 10, it is entirely possible that changes in expression of MHCI in the developing brain caused by environmental insults contribute to the cellular changes that cause these disorders. The central goal of this proposal is to determine the function of MHCI proteins during the initial formation of connections in the early postnatal brain, a comparable developmental stage to the time of the immune challenge proposed to predispose humans toward neurodevelopmental disorders.

描述（由申请人提供）：尽管多年来一直有证据表明免疫系统和神经系统之间存在相互作用，但免疫分子在正常发育的神经系统中具有非免疫功能的观点最近才得到证实。这一想法是基于以下观察：适应性免疫反应的主要介质，主要组织相容性复合物I类（MHCI）分子，在大脑中表达，它们介导连接的活性依赖性细化。MHCI分子也是异常或强免疫应答对发育中的大脑的影响的分子介质的有吸引力的候选物，其已经涉及几种神经发育障碍（包括自闭症和精神分裂症）的发病机制。这项提议的中心目标是确定MHCI在皮质连接最初建立期间的功能，这是一个与免疫挑战时间相当的发育阶段，可能使人类倾向于神经发育障碍。使用免疫细胞化学和组织化学，电子显微镜，细胞和切片培养和转染，一种新的长期成像分析，和全细胞膜片钳记录，我们将解决以下目标。(1)确定皮质发育过程中MHCI分子在体内和体外的定位。(2)验证MHCI分子在体内和体外调节皮质连接的初始建立和功能的假设。(3)确定MHCI分子是否通过抑制突触形成、增加突触消除或两者来负性调节皮质连接的建立。(4)验证MHCI分子通过自然杀伤细胞受体负调控皮层连接建立的假设。这项提议的结果应该揭示MHCI在典型发育中的大脑中的新功能，以及它们如何有助于大脑发育的潜在机制。神经发育障碍公共卫生相关性：虽然已经提出了广泛的环境刺激在神经发育障碍（包括自闭症和精神分裂症）的发病机制中发挥作用，但这些刺激中的许多都具有改变免疫功能的能力。由于MHCI分子启动和介导免疫应答9并且存在于脑10中，因此完全可能的是，由环境损伤引起的发育中的脑中MHCI表达的变化有助于引起这些病症的细胞变化。这项建议的中心目标是确定MHCI蛋白在出生后早期大脑连接最初形成过程中的功能，这是一个与免疫挑战的时间相当的发育阶段，建议使人类倾向于神经发育障碍。