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

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。

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.