Down syndrome: Bridging Genes and Neural Pathways

唐氏综合症：连接基因和神经通路

基本信息

批准号：
7177523
负责人：
JULIE RUTH KORENBERG
金额：
$ 32.18万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-06-12 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7177523
关键词：
Affect Aggressive behavior Aging Alzheimer&apos s Disease Amygdaloid structure Aneuploidy Antibodies Architecture Attention Basal Ganglia Behavior Behavioral Brain Breeding Calcium Calmodulin Cell Line Cell model Cells Cellular biology Cerebellum Cerebral cortex Cholinergic Agents Chromosomes, Human, Pair 21 Cognition Collaborations Consult Data Dendrites Dendritic Spines Development Down Syndrome Estrogens Female Funding Gene Expression Genes Goals Golgi Apparatus Habenula Hippocampal Formation Hippocampus (Brain)Human Immunohistochemistry Knockout Mice Lateral Lead Learning Limbic System Literature Localized Macaca Measures Medial Mediating Medicine Memory Mental Retardation Modeling Monkeys Mus Neocortex Nerve Degeneration Neural Pathways Neurobiology Neurons Numbers Pathway interactions Pattern Persons Phenotype Phosphorylation Population Prefrontal Cortex Prosencephalon Protein Overexpression Proteins Purkinje Cells Quantitative Reverse Transcriptase PCR Regulation Reporting Research Resources Role Series Signal Pathway Silver Social Behavior Staining method Stains Structure Structure of subthalamic nucleus Study Section System Techniques Testing Transgenes Transgenic Mice Transgenic Organisms Trees Trisomy Universities Work base behavior observation behavior test brain behavior cholinergic dentate gyrus design fly human Huntingtin protein human disease insight male mouse model neuronal cell body neuroprotection nonhuman primate novel novel strategies promoter protein expression putamen relating to nervous system research study success

项目摘要

A. Specific Aims The ultimate goal of our research is to elucidate the pathways underlying the altered neurobiology of Down syndrome, focusing on neocortex and hippocampus. The past decade has focused on sequencing chromosome 21, evaluating gene expression in cell lines and trisomic mouse models, identifying signaling pathways involving chromosome 21 genes, and looking at the effects of segmental trisomy in mouse, on cellular, neuroanatomic and behavioral phenotypes. The results of these studies may lead to new approaches to ameliorate the deleterious effects of these genes on development and cognition in DS. Systems Medicine: Our work provides insights that support a fundamental change in the approach to mental retardation, from orientation on single components to the use of a broader, neural systems based approach to identify common pathways that may underly a spectrum of MR in humans. Beginning with humans with partial trisomy for 21, we identified regions and then single genes likely involved in MR in DS and then generated single gene mouse models, relating findings to humans with aneuploidy for 21. In the current year, we have identified expression patterns and abnormalities in the brains of these mice (and in our other chromosome 21 models), at the level of brain structure, the dendritic tree, dendritic spine, behavior and cell biology (additional model), and have begun to generate fly models of the same subset of DS genes, and to investigate their gene expression in non-human primates. Combining the data from DS and mouse models suggests that disturbances of a smaller number of common developmental pathways may underly a broader spectrum of MR and focus models in which to test these. It is important to note that the recent report of a mouse model generated with sequences originating from human (not mouse) chromosome 21 (Fisher and "^Progress has been made in all aims, with exciting accomplishments including the knock-out mouse for dscam, the establishment of fly models for DS/ chromosome 21 genes, the beautiful Golgi Staining for dendrites, spines and neuronal systems altered in the Pcp4/ PEP19 transgenic, the identification of meso-limbic system expression of Pcp4/PEP19Jn mouse, and finally, emerging from this findings produced by this proposal, but beyond the funded scope, expression in limbic system of Macaque fasicularis (monkey), and preliminary evidence in DS for abnormal specific neuronal populations in human prefrontal cortex. Accomplishments and plans are listed under each aim.

A.具体目标我们研究的最终目的是阐明改变的神经生物学基础的途径唐氏综合症，专注于新皮层和海马。过去十年的重点是测序染色体21，评估细胞系和三化小鼠模型中的基因表达，识别信号涉及21个基因的途径，并查看小鼠中节段三体的影响，细胞，神经解剖和行为表型。这些研究的结果可能导致新的改善这些基因对DS发育和认知的有害影响的方法。系统医学：我们的工作提供了支持智力低下方法的根本变化的见解，从单个组件的定位到使用基于更广泛的，基于神经系统的方法来识别在人类中可能基本MR的常见途径。从人类开始三体性为21，我们确定了区域，然后可能参与DS中的MR，然后产生单基因小鼠模型，将发现与四倍的人类有关，为21。在本年度，我们有这些小鼠的大脑中鉴定出的表达模式和异常（在我们的其他染色体中 21个模型），在大脑结构水平，树突树，树突状脊柱，行为和细胞生物学（附加模型），并已开始生成同一DS基因子集的苍蝇模型，并研究其在非人类灵长类动物中的基因表达。结合DS和鼠标模型的数据表明少数常见发展途径的干扰可能会更广泛在其中测试这些模型的MR和焦点模型的频谱。重要的是要注意，最近的报告小鼠模型由序列产生的序列来自人类（不是小鼠）染色体21（费舍尔和 “^在所有目标中都取得了进步，并取得了令人兴奋的成就对于DSCAM，建立用于DS/染色体21个基因的飞行模型，美丽的高尔基染色对于pCP4/ PEP19转基因中改变的树突，刺和神经元系统的鉴定 pcp4/pep19jn鼠标的中边缘系统表达，最后是从此发现中出现的由该提案产生，但超出了资助的范围，在猕猴的边缘系统中的表达 Fasicularis（猴子）和DS中异常特异性神经元种群的初步证据人前额叶皮层。每个目标都列出了成就和计划。