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Selective disruption of hippocampal dentate granule cells in autism: impact of PT

自闭症患者海马齿状颗粒细胞的选择性破坏：PT 的影响

基本信息

批准号：
8411855
负责人：
Steve C Danzer
金额：
$ 1.46万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8411855
关键词：
Adult Age Animal Testing Animals Autistic Disorder Automobile Driving Behavior Behavioral Birth Brain Brain Part Brain imaging Brain region Cells Cerebellum Characteristics Child Childhood Cognition Cognitive deficits Dendrites Development Diagnosis Diphtheria Toxin Disease Electroencephalography Embryo Epilepsy Exhibits Gene Expression Generations Genes Growth Health Hippocampus (Brain)Human Immediate-Early Genes Impairment Infection Knock-out Language Language Development Lead Learning Memory Monitor Mus Mutate Mutation Nature Neurocognitive Deficit Neurodevelopmental Disorder Neurons Newborn Infant PI3K/AKT PTEN gene Pathway interactions Patients Pattern Pilot Projects Play Population Prevalence Reporter Resistance Role Seizures Sonic Hedgehog Pathway Symptoms Tamoxifen Technology Temporal Lobe Epilepsy Testing Thick Time Toxin Transgenic Mice Vertebral column Withdrawal autistic children brain cell communication behavior density dentate gyrus diphtheria toxin receptor effective therapy granule cell infancy insight interest member mossy fiber mouse model novel postnatal prevent progenitor promoter receptor expression recombinase social virtual white matter

项目摘要

DESCRIPTION (provided by applicant): During the development of a child, most brain cells are generated before birth. There is one group of brain cells, however, that are generated in large numbers in infancy. This occurs in a brain region called the hippocampus. These cells are important for the normal development of memory, cognition and language, and disruption of these cells is present in children with autism. Disruption of these cells may also contribute to the prevalence of epilepsy in children with autism. Although it makes sense that these cells are responsible for key features of autism, children with the disease exhibit changes in many other parts of the brain as well. Our limited understanding of which changes are important, unfortunately, has slowed progress in the field. In the present proposal, therefore, we will examine the impact of eliminating a gene known to be involved in autism on these late-generated cells. These studies will reveal whether selectively disrupting these cells can reproduce features of autism. Demonstrating that these cells play an important role in the development of autism (or associated conditions like epilepsy), will provide a compelling rationale to develop new therapies to protect these vulnerable cells. In addition, since these cells are born so late in development, and are actually produced through childhood and into adulthood, it may be possible to prevent the disruption of cells born after a diagnosis of autism and thus allow the brain to naturally restore itself. It is our hope that these studies will move us closer to developing new and more effective treatments for autism. PUBLIC HEALTH RELEVANCE: The proposed studies seek to better elucidate the causes of autism by determining whether selective disruption of late-generated neurons - specifically hippocampal dentate granule cells - contributes to key features of autism. This will be achieved using a novel combination of transgenic mice to selectively eliminate a gene implicated in autism from these late-generated neurons. Significantly, although the proximal cause of autism remains to be determined in most cases, the late generation of these neurons (in the late embryonic period and in infancy) may make them uniquely vulnerable to a variety of insults faced by the newborn child (e.g. infection). The proposal will also examine the role of granule cells in the development of epilepsy, the condition most commonly associated with autism.

描述（由申请人提供）：在儿童的发育过程中，大多数脑细胞在出生前产生。然而，有一组脑细胞在婴儿期大量产生。这发生在大脑中一个叫做海马体的区域。这些细胞对记忆、认知和语言的正常发育很重要，自闭症儿童存在这些细胞的破坏。这些细胞的破坏也可能导致自闭症儿童癫痫的患病率。虽然这些细胞负责自闭症的关键特征是有道理的，但患有这种疾病的儿童在大脑的许多其他部位也表现出变化。不幸的是，我们对哪些变化是重要的了解有限，这减缓了该领域的进展。因此，在本提案中，我们将研究消除已知与自闭症有关的基因对这些后期生成细胞的影响。这些研究将揭示选择性地破坏这些细胞是否可以复制自闭症的特征。证明这些细胞在自闭症（或癫痫等相关疾病）的发展中起着重要作用，将为开发新的疗法来保护这些脆弱的细胞提供令人信服的理由。此外，由于这些细胞在发育后期出生，并且实际上是在儿童期和成年期产生的，因此有可能防止自闭症诊断后出生的细胞受到破坏，从而使大脑自然恢复。我们希望这些研究将使我们更接近开发新的和更有效的自闭症治疗方法。公共卫生相关性：拟议中的研究试图通过确定选择性破坏晚期生成的神经元-特别是海马齿状颗粒细胞-是否有助于自闭症的关键特征来更好地阐明自闭症的原因。这将通过使用一种新的转基因小鼠组合来实现，以选择性地从这些后期生成的神经元中消除与自闭症有关的基因。值得注意的是，虽然在大多数情况下自闭症的近端原因仍有待确定，但这些神经元的晚期（在胚胎晚期和婴儿期）可能使它们特别容易受到新生儿所面临的各种伤害（例如感染）。该提案还将研究颗粒细胞在癫痫发展中的作用，癫痫是最常见的与自闭症相关的疾病。