权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
8013631
负责人：
A Kimberley McAllister
金额：
$ 32.61万
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/8013631
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 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）：尽管免疫系统和神经系统之间的串扰多年来一直有证据，但免疫分子在正常发育的神经系统中具有非免疫功能的想法直到最近才得到证实。这个想法是基于对适应性免疫反应的主要介质，主要组织相容性复合体I类（MHCI）分子的观察，这些分子在大脑中表达，在那里它们介导活动依赖性的连接改进。MHCI分子也是异常或强烈免疫反应对发育中的大脑影响的分子介质的有吸引力的候选者，这与包括自闭症和精神分裂症在内的几种神经发育障碍的发病机制有关。该提案的中心目标是确定MHCI在皮层连接初始建立期间的功能，这是一个与免疫挑战时期相当的发育阶段，可能使人类易患神经发育障碍。使用免疫细胞和组织化学，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，全细胞膜片钳记录，我们将解决以下目标。(1)确定皮层发育过程中MHCI分子在体内和体外的定位。(2)在体内和体外验证MHCI分子调控皮层连接的初始建立和功能的假说。(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兼而有之负调控皮层连接的建立。(4)验证MHCI分子通过自然杀伤细胞受体负向调控皮层连接建立的假说。这一建议的结果将揭示MHCI在典型发育的大脑中的新功能，以及它们如何促进的潜在机制