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Supplement to TR01 Human cortical development and neural plasticity altered by trisomy 21

TR01 补充品 21 三体改变的人类皮质发育和神经可塑性

基本信息

批准号：
10670626
负责人：
ANITA BHATTACHARYYA
金额：
$ 18.62万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-12 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10670626
关键词：
3-Dimensional Adult Affect Anatomy Award Biological Brain Cell Culture Techniques Cells Chromosome 21 Cognition Cognitive Complex Defect Dendritic Spines Development Developmental Process Disease Down Syndrome Electrophysiology (science)Ensure Equipment Exhibits Foundations Functional disorder Funding Future Genes Genetic Genetic Transcription Glutamates Hippocampus (Brain)Human Human Chromosomes Human Genetics Impaired cognition Impairment In Vitro Incubators Individual Induced pluripotent stem cell derived neurons Intellectual functioning disability Interneurons Intervention Lead Long-Term Potentiation Maintenance Mental Depression Modeling Molecular Molecular Profiling Motor Mus Neuronal Differentiation Neuronal Dysfunction Neuronal Plasticity Neurons Parents Pathway interactions Population Pregnancy Process Public Health Research Resources Sampling Signal Transduction Synapses Synaptic Transmission Synaptic plasticity Temporal Lobe Therapeutic Intervention Transcriptional Regulation Work base cell type cost design developmental disease developmental genetics excitatory neuron experimental study frontal lobe gamma-Aminobutyric Acid gene regulatory network induced pluripotent stem cell inhibitory neuron insight mouse development mouse model neurodevelopment neurogenesis neuron development neuronal excitability postnatal prenatal progenitor programs social stem cell differentiation stem cell model synaptogenesis three dimensional cell culture

项目摘要

ABSTRACT Down syndrome (DS, trisomy 21, T21), a complex multigene disorder and the most common genetic cause of intellectual disability. However, surprisingly little is known about the underlying mechanisms that lead to cognitive impairment in DS. There are fewer neurons in adult DS cortex and reduced neurogenesis and synaptogenesis have been implicated as features of DS development. Yet, what and how specific neurons and synaptic contacts are affected at which period of development and what molecular pathways underlie these defects that lead to intellectual disability remain unclear. The parent award was funded to build models based on human induced pluripotent stem cells (iPSCs), to interrogate how T21 disrupts developmental processes in DS. The iPSC model will be validated by integrating cellular changes and molecular signatures of single cells in vitro with DS prenatal cortex. The parent award relies on maintenance, differentiation and analysis of iPSC derived neurons in vitro for two of the three Aims. This supplement requests funding for cell culture related equipment that is required to carry out Aims 2 and 3 of the parent award. Funding is requested to replace two cell culture incubators for maintenance of iPSCs and differentiated neurons in Aim 2 and 3. Funding is also requested for an additional electrophysiological rig for analysis of iPSC derived neurons in Aim 3. The parent award included minimal equipment funding and these costs were unforeseen when the application was awarded.

摘要唐氏综合征(DS，21三体，T21)，一种复杂的多基因疾病，是智力残疾。然而，令人惊讶的是，人们对导致认知能力的潜在机制知之甚少。 DS中的损害。成年DS皮层神经元减少，神经发生和突触发生减少。已经被认为是DS发展的特征。然而，具体的神经元和突触接触是什么以及如何进行的在发育的哪个时期受到影响，以及导致这些缺陷的分子途径是什么智力障碍仍不清楚。家长奖的资金用于构建基于人类诱导的模型多能干细胞(IPSCs)，以询问T21如何扰乱DS的发育过程。IPSC模式将通过将体外单个细胞的细胞变化和分子特征与胎儿DS结合起来进行验证大脑皮层。Parent奖依赖于IPSC来源的神经元在体外的维护、分化和分析三个目标中的两个。本补充要求为细胞培养相关设备提供资金，以满足执行家长奖励的目标2和目标3。申请资金以更换两个细胞培养孵化器维持Aim 2和Aim 3的IPSCs和分化神经元。还要求提供额外的经费用于分析AIM 3中IPSC来源的神经元的电生理装置。设备经费和这些费用在授予申请书时是预料不到的。