Down syndrome: Bridging Genes, Brain and Cognition

唐氏综合症：连接基因、大脑和认知

基本信息

批准号：
8492122
负责人：
GUIDO GERIG
金额：
$ 55.37万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-10 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8492122
关键词：
Address Affect Age Alzheimer&apos s Disease Anatomy Aneuploidy Animal Model Atherosclerosis Auditory Basic Science Brain Brain Diseases Brain imaging Brain region Cerebellum Child Chromosome Mapping Chromosomes, Human, Pair 21 Clinical Research Cognition Cognitive Cognitive deficits Congenital Abnormality Defect Development Developmental Disabilities Diffusion Magnetic Resonance Imaging Direct Costs Disease Down Syndrome Drug Targeting Event Exons Face Facilities and Administrative Costs Family Fiber Functional Imaging Gender Genes Genetic Genetic screening method Genome Glutamate Metabolism Pathway Glutamates Goals Heart Hippocampus (Brain)Human Human Development Human Genome Image Individual Intellectual functioning disability Intervention Knowledge Language Language Tests Life Link Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Maps Measures Medical Memory Mental Retardation Modeling Monozygotic twins Mus NMR Spectroscopy Neuroanatomy Neurobiology Neurocognition Neurocognitive Neurocognitive Deficit Neurosciences Neurotransmitters Pathway interactions Performance Persons Phenotype Prefrontal Cortex Prevention Process Psyche structure Recovery Reporting Research Resolution Resources Risk Scientist Social Welfare Solid Neoplasm Speech Structure System Techniques Technology Testing Time Trisomy Trisomy 17 Work cognitive function cohort congenital heart disorder cost disability discount duplicate genes gamma-Aminobutyric Acid genetic analysis genome sequencing in vivo innovation insight interdisciplinary approach leukemia lymphoblastoid cell line malformation mental age neural circuit neurocognitive test neuroimaging novel relating to nervous system success treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Down syndrome (DS) or trisomy for chromosome 21, is a major cause of mental retardation and congenital heart disease, that affects more than 400,000 individuals in the USA. In addition, people with DS have defects in memory, language and neuroanatomy. The ultimate goal of this proposal is to elucidate the genes, neuroanatomy and neurocircuitry linked to the neurocognitive defects of DS. Recent advances in human genome sequencing provide a complete list of chromosome 21 genes, but until recently (Korbel, 2009), there were no genes linked to any specific feature and no successful treatment for the cognitive deficits. Treatment of DS has been hindered by lack of human models for narrowing the genes responsible for cognitive features, the need for high resolution neuroimaging of the brain defects in DS and the need for cognitive tests focused on DS deficits. To address these gaps, we propose an innovative multidisciplinary approach integrating neuroimaging, cognitive testing and genetics. In DS as in genetics, rare events can illuminate common processes. Rare individuals have DS caused by duplication of only parts of chromosome 21 and provide a unique opportunity to link the defects of brain development and function with the genes responsible. The PI of this proposal has generated the largest cohort in existence, consisting of 45 persons, of whom 30 are alive, in the USA, 27 aneuploid only for 21. Recently, these rare cases were used to map specific gene subsets in DS for congenital malformations but little was known about the brain or cognition. Further, a unique and rare set of identical twins discordant for DS, has been identified and studied. To characterize these cohorts, a unique team of scientists has been created, with expertise in partial trisomy 21 (Korenberg), neurocognitive testing targeted to DS (Nadel, Yurgelun-Todd), Magnetic Resonance Imaging and Diffusion tensor imaging (Yurgelun- Todd, Gerig), NMR Spectroscopy (Renshaw) and genome organization (Korenberg). This team will integrate high resolution imaging of full and rare partial trisomy 21 to establish the regional neuroanatomy and neurocircuitry of DS and to link these to subsets of chromosome 21 genes. We will test three levels of hypotheses, first to define in DS vs normals, distinct volumetric and circuit brain structures and defects of cognitive function, including language and memory; second, to link within DS, neural substrates with cognitive features and third, by using each rare partial trisomy, to begin to parse gene subsets for DS neural and cognitive features. Further, we will test in DS, whether the glutamatergic or, as in mouse, the GABAergic neurotransmitter systems are disturbed in vivo. We propose two aims: 1) to characterize 60 normal and 60 full trisomy 21 individuals with cognitive testing, high resolution MRI, DTI and MRS, 2) to characterize the rare DS cohort with partial trisomy 21 and the unique set of identical twins discordant for DS as in aim 1. The results of these studies will provide unprecedented knowledge of the defects of brain development and function in DS, GABAergic and glutamatergic pathways, and the relationship of both to genes duplicated. These results will help to elucidate the neurobiology of DS and to develop novel treatments for DS and other intellectual disabilities.

描述（由申请人提供）：染色体21的唐氏综合症（DS）或三体疾病是智力低下的主要原因和先天性心脏病，影响了美国超过40万人。此外，具有DS的人在记忆，语言和神经解剖学方面存在缺陷。该提案的最终目标是阐明与DS神经认知缺陷相关的基因，神经解剖和神经记录。人类基因组测序的最新进展提供了21个染色体基因的完整列表，但直到最近（Korbel，2009年），没有与任何特定特征有关的基因，并且没有成功治疗认知缺陷。缺乏人类模型来缩小导致认知特征的基因，对DS中大脑缺陷的高分辨率神经影像的需求以及对DS缺陷的认知测试的需求，这阻碍了DS的治疗。为了解决这些差距，我们提出了一种创新的多学科方法，以整合神经影像学，认知测试和遗传学。在DS中，就像在遗传学中一样，罕见事件可以照亮常见过程。罕见的个体具有仅重复21号染色体的重复引起的DS，并提供了一个独特的机会，可以将脑发育和功能的缺陷与负责的基因联系起来。该提案的PI产生了现有的最大人群，由45人组成，其中30人在美国还活着，只有27个非整倍型。最近，这些稀有病例用于绘制先天性畸形中DS的特定基因亚群，但对大脑或认知知之甚少。此外，已经确定和研究了一组独特而罕见的双胞胎与DS不一致的双胞胎。 To characterize these cohorts, a unique team of scientists has been created, with expertise in partial trisomy 21 (Korenberg), neurocognitive testing targeted to DS (Nadel, Yurgelun-Todd), Magnetic Resonance Imaging and Diffusion tensor imaging (Yurgelun- Todd, Gerig), NMR Spectroscopy (Renshaw) and genome organization (Korenberg).该团队将整合完全和罕见的部分三体术的高分辨率成像，以建立DS的区域神经解剖学和神经记录，并将其与21个染色体基因的子集联系起来。我们将测试三个级别的假设，首先是在DS与正常情况下定义的，这些假设，包括语言和记忆在内的认知功能的不同体积和电路的大脑结构以及缺陷；其次，为了在DS内链接，具有认知特征的神经底物，第三，通过使用每个罕见的部分三体三体，开始解析DS神经和认知特征的基因子集。此外，我们将在DS中测试，无论是谷氨酸能或小鼠中的GABA能神经递质系统在体内受到干扰。我们提出了两个目的：1）表征60个正常和60个全三体21个认知测试，高分辨率MRI，DTI和MRS，2）的表征，表征了罕见的DS队列21分三体三体，而独特的双胞胎对DS的独特双胞胎则为AIM 1。谷氨酸能途径，以及两种复制基因的关系。这些结果将有助于阐明DS的神经生物学，并为DS和其他智力残疾开发新的治疗方法。