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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标是阐明神经生物学改变的潜在途径，唐氏综合症，集中在新皮层和海马体。过去十年的重点是测序染色体21，评估细胞系和三体小鼠模型中的基因表达，鉴定信号传导涉及21号染色体基因的通路，并观察小鼠节段性三体的影响，细胞、神经解剖学和行为表型。这些研究的结果可能会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：我们的工作提供了一些见解，支持从根本上改变精神发育迟滞的方法，从单一组件的定位到使用更广泛的基于神经系统的方法来识别可能是人类MR谱的基础的共同途径。从人类开始，对于21三体，我们确定了可能参与DS MR的区域，然后确定了可能参与DS MR的单个基因，单基因小鼠模型，与21.今年，我们有在这些小鼠的大脑中（以及我们的另一条染色体中）确定了表达模式和异常 21模型），在大脑结构的水平，树突树，树突棘，行为和细胞生物学（额外的模型），并已开始产生相同的DS基因子集的苍蝇模型，并研究它们在非人类灵长类动物中的基因表达。结合DS和小鼠模型的数据这表明，少数共同发育途径的障碍可能是更广泛的发育障碍的基础。用于测试这些的MR和焦点模型的频谱。值得注意的是，最近的一份报告指出，用源自人（非小鼠）21号染色体的序列产生的小鼠模型（Fisher和 “^所有目标都取得了进展，取得了令人兴奋的成就，包括敲除小鼠对于dscam，建立果蝇DS/21号染色体基因模型，进行美丽的高尔基染色对于在Pcp 4/PEP 19转基因中改变的树突、棘和神经元系统， Meso-limbic system expression of Pcp4/PEP19Jn mouse，and finally，emerging from this findings 本提案产生，但超出资助范围，猕猴边缘系统表达 fascicularis（猴），以及DS中异常特定神经元群体的初步证据，人类前额皮质在每个目标下列出了成就和计划。