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Project-004

项目-004

基本信息

批准号：
10686445
负责人：
Michael Craig Carroll
金额：
$ 69.15万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686445
关键词：
Address Adolescence Adolescent Adolescent Development Adult Astrocytes Autopsy Basal Ganglia Behavior Behavioral Biological Biological Assay Biological Models Biology Brain Brain region CD47 gene Callithrix Cell model Cells Cellular Assay Cognition Cognitive Complement Complement component C4 Complement component C4a Complex Decision Making Development Disease Distant Environment Environmental Risk Factor Etiology Functional disorder Gene Expression Generations Genes Genetic Genetic Risk Genetic Transcription Genomics Goals Human Immune Immunology Incidence Individual Intervention Investigation Link Maps Mediating Mental Health Mental disorders Modeling Molecular Multimedia Mus Neuroanatomy Neurodevelopmental Disorder Neuroimmune Neuroimmunomodulation Neurons Neurosciences Outcome Parents Pathway interactions Persons Pharmacology Phenotype Physiological Physiology Play Population Research Research Personnel Resources Rewards Risk Risk Assessment Risk Factors Role Route Sampling Schizophrenia Shapes Signal Transduction Social Behavior Social Workers Source Specificity Synapses Testing Thalamic structure Therapeutic Tissue Model Training Work adolescent brain development behavioral phenotyping brain tissue cell type childhood adversity cognitive development course development critical period frontal lobe human stem cells human tissue innovation interdisciplinary collaboration interest member mouse model neuropsychiatry non-genetic nonhuman primate novel novel diagnostics novel strategies novel therapeutic intervention outreach overexpression postnatal psychiatric symptom psychogenetics relating to nervous system response risk variant schizophrenia risk social symposium synaptic function synaptic pruning synaptogenesis teacher therapeutic evaluation tool training opportunity transcriptome vulnerable adolescent web site young adult

项目摘要

The pathophysiology of schizophrenia has been unknown, resulting in a lack of innovative therapeutics with novel mechanisms of action. The Conte Center for Neuroimmune Studies was created to build on our discovery that the biology underlying the most significant schizophrenia common genetic risk variants involves neuroimmune mechanisms of synaptic pruning. We have found that risk variants of the complement component C4 genes are correlated with increased C4A expression in the brain and CSF, and that overexpression of human C4A in a mouse model results in excess synaptic pruning and social behavioral deficits. We have further shown that additional neuroimmune molecules encoded at schizophrenia risk loci, CD47 and CSMD1, influence synaptic pruning and complement activity. Lastly, schizophrenia is unusual among neurodevelopmental disorders in its late-adolescent/early-adult onset, and childhood adversity is a major non-genetic risk factor for schizophrenia; yet the biological underpinnings of adolescent psychiatric vulnerability are wholly unknown. We have identified a critical period of circuit refinement in the mouse frontal cortex that we propose can be exploited to better understand the unique vulnerability of adolescent brain development to psychiatric risk factors. The goals of the Center in our next five years are to both deepen the focus on C4-mediated synaptic pruning as a pathophysiological mechanism, and expand the scope of our investigations to create a fuller picture of neuroimmune pathways, their upstream regulators, their cellular effectors, and their downstream circuit-level and behavioral impacts. Project 1 will investigate the role of astrocytes, the main source of C4 in the brain, by manipulating schizophrenia risk genes in these cells and assaying the impacts on synapse formation and function. Project 2 will spatially map the brain’s transcriptional response to C4 overexpression, and test the therapeutic hypothesis that inhibition of C4 activity may rescue over-pruning and associated behavioral phenotypes. Project 3 will examine the circuit specificity of the adolescent critical period, the impacts of gene-by-environment risk factor interactions, and the roles of the brain borders. Project 4 will explore circuit-level interactions between the basal ganglia and frontal cortex in the context of adolescent development, psychiatric risk factors, and risk/reward decision-making. We will also lay the groundwork for expanding neuroimmune studies of psychiatric risk to a non-human primate model, the marmoset. Finally, our Administrative Core will facilitate interdisciplinary collaboration that exploits the full range of expertise across the four labs, and coordinate outward- facing activities including the annual research symposium.

精神分裂症的病理生理机制一直不清楚，导致缺乏创新具有新作用机制的治疗学。康特神经免疫研究中心是是基于我们的发现而创建的，即最重要的精神分裂症背后的生物学常见的遗传风险变异涉及突触修剪的神经免疫机制。我们有发现补体成分C4基因的风险变异与增加相关 C4a在脑和脑脊液中的表达，以及在小鼠模型中人类C4a的过表达会导致过度的突触修剪和社会行为缺陷。我们已经进一步表明，精神分裂症危险基因CD47和CSMD1上编码的其他神经免疫分子，影响突触修剪和补体活性。最后，精神分裂症在青春期晚期/成年早期的神经发育障碍，儿童时期的逆境精神分裂症的主要非遗传风险因素；然而青少年的生物学基础精神上的脆弱性是完全未知的。我们已经确定了一个关键的巡回周期我们提出的小鼠额叶皮质的精细化可以被用来更好地理解青少年大脑发育对精神危险因素的独特脆弱性。该中心未来五年的目标是深化对C4中介的关注突触修剪作为一种病理生理机制，并扩大了我们的研究范围为了更全面地了解神经免疫途径，它们的上游调节因子，它们的细胞效应器及其下游电路级和行为影响。项目1将调查大脑中C4的主要来源--星形胶质细胞通过操纵精神分裂症危险基因所起的作用并分析其对突触形成和功能的影响。项目2将在空间上绘制大脑对C4过度表达的转录反应图，并测试治疗 C4活性抑制可能挽救过度修剪和相关行为的假说表型。项目3将检查青少年关键期的电路特异性，即基因与环境风险因素相互作用的影响，以及大脑边界的作用。项目 4将在此背景下探索基底神经节和额叶皮质之间的电路水平相互作用青少年发展、精神风险因素和风险/回报决策。我们还将为将精神疾病风险的神经免疫研究扩展到非人类奠定基础灵长类动物模型，绒猴。最后，我们的行政核心将促进跨学科协作利用四个实验室的所有专业知识，并向外协调- 面向包括年度研究研讨会在内的活动。