Down syndrome: Bridging Genes, Brain and Cognition

唐氏综合症：连接基因、大脑和认知

• 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
• 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' 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

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）：唐氏综合征（DS）或21号染色体三体，是精神发育迟滞和先天性心脏病的主要原因，在美国影响超过40万人。此外，DS患者在记忆、语言和神经解剖学方面存在缺陷。这项建议的最终目标是阐明与DS的神经认知缺陷相关的基因、神经解剖学和神经回路。人类基因组测序的最新进展提供了21号染色体基因的完整列表，但直到最近（Korbel，2009），还没有与任何特定特征相关的基因，也没有成功治疗认知缺陷的方法。由于缺乏缩小认知功能基因的人类模型，需要对DS中的脑缺陷进行高分辨率神经成像，以及需要对DS缺陷进行认知测试，因此DS的治疗受到阻碍。为了解决这些差距，我们提出了一种创新的多学科方法，将神经成像，认知测试和遗传学相结合。在DS中，就像在遗传学中一样，罕见的事件可以阐明共同的过程。罕见的个体患有由21号染色体部分重复引起的DS，并提供了将大脑发育和功能缺陷与相关基因联系起来的独特机会。该提案的PI已经产生了现有的最大队列，包括45人，其中30人还活着，在美国，27非整倍体仅为21。最近，这些罕见的情况下，被用来映射特定的基因子集在DS的先天性畸形，但鲜为人知的大脑或认知。此外，一个独特的和罕见的同卵双胞胎不一致的DS，已被确定和研究。为了表征这些队列，创建了一个独特的科学家团队，他们具有部分21三体（Korenberg）、针对DS的神经认知测试（Nadel，Yurgelun-托德）、磁共振成像和扩散张量成像（Yurgelun-托德，Gerig）、NMR光谱学（Renshaw）和基因组组织（Korenberg）的专业知识。该团队将整合完整和罕见的部分21三体的高分辨率成像，以建立DS的区域神经解剖学和神经回路，并将其与21号染色体基因的子集联系起来。我们将测试三个层次的假设，首先定义在DS与正常人，不同的体积和电路脑结构和认知功能的缺陷，包括语言和记忆;第二，在DS，神经基板与认知功能和第三，通过使用每个罕见的部分三体，开始解析基因子集的DS神经和认知功能。此外，我们将测试在DS中，是否多巴胺能或，如在小鼠中，GABA能神经递质系统在体内受到干扰。我们提出两个目标：1）通过认知测试、高分辨率MRI、DTI和MRS表征60名正常和60名完全21三体个体，2）表征具有部分21三体的罕见DS队列和与DS不一致的独特同卵双胞胎组，如目的1所述。这些研究的结果将提供前所未有的知识，在DS，GABA能和谷氨酸能途径的大脑发育和功能的缺陷，以及两者与基因复制的关系。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。