Project 4: Berto

项目4：贝托

• 批准号: 10556545
• 负责人: Stefano Berto
• 金额: $ 22.65万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556545
• 关键词: Affect; Age; Alleles; Animal Model; Animals; Attention deficit hyperactivity disorder; Behavior; Behavioral; Bioinformatics; Biological Models; Biological Process; Brain; CRISPR/Cas technology; Cell Adhesion Molecules; Cell model; Centers of Research Excellence; Child; Cognition; Data; Development; Disease; Electroencephalography; Electrophysiology (science); Environment; Epilepsy; Episodic memory; Face; Family; Frequencies; Future; Generations; Genes; Genetic Transcription; Genomics; HLA Antigens; Human; Image; Impaired cognition; Intellectual functioning disability; Interleukin Receptor; Interleukin-1; Investigation; Knockout Mice; Link; Measures; Memory; Messenger RNA; Mission; Molecular; Mutation; Neuroanatomy; Neurodevelopmental Disorder; Neurons; PTPRR gene; Pattern; Phenotype; Play; Protein Tyrosine Phosphatase; Publishing; Regulation; Research Personnel; Resources; Risk; Role; Short-Term Memory; Signal Pathway; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; United States; United States National Institutes of Health; Vertebral column; Visual; autism spectrum disorder; behavioral phenotyping; career development; density; disorder risk; excitatory neuron; hearing impairment; human subject; induced pluripotent stem cell; innovation; loss of function; loss of function mutation; motor impairment; mouse model; multidisciplinary; neurodevelopment; neuronal excitability; neurotransmitter release; novel; paralogous gene; programs; receptor; risk variant; single nucleus RNA-sequencing; social; synaptic function; synaptogenesis; transcriptomics

PROJECT 4 – SUMMARY Neurodevelopmental disorders (NDDs) are caused by abnormal development of molecular and synaptic networks in the brain and are characterized by developmental behavioral deficits with clear social and cognitive impairments. Approximately 15% of children in the United States ages 3 to 17 years are affected by NDDs which include autism spectrum disorders (ASD), attention-deficit hyperactivity disorder (ADHD), epilepsy, intellectual disability (ID), hearing impairments, visual/motor impairments, among others. Interestingly, NDDs, in particular ASD and ID, are also marked by a number of memory-related deficits, such as face identity recognition, working memory, and episodic memory. Nevertheless, the link between genes, memory phenotypes, and NDDs is poorly understood. This project focuses on the function of the NDD risk gene, IL1RAPL2, in human iPSC-derived excitatory neurons and in ASD-like and memory behaviors using a newly developed mouse model. We hypothesize that IL1RAPL2 plays a key role in neurodevelopmental disorders and memory phenotypes by regulating synapse development on cortical excitatory neurons. Aim 1 will take advantage of human IPSC- derived deep layer excitatory neurons with IL1RAPL2 loss-of-function (LoF) to understand its function in the transcriptomic landscapes, in regulation of dendritic arborization and spine density, and in neuronal excitability and synaptic transmission. Aim 2 will take advantage of a new mouse model with a global Il1rapl2 LoF to mimic LoF mutations in humans, that will enable an understanding of its role in NDDs and memory related behaviors. The NIH COBRE in Neurodevelopment and Its Disorders (CNDD) will provide an ideal environment, critical resources and Cores, and career development opportunities to enable the successful transition of Dr. Berto to an established, independent investigator at MUSC. Moreover, the proposed studies, and approaches employed, are important and highly relevant to the mission and theme of the CNDD, and the Project data will prepare Dr. Berto for a future competitive R01 application.

项目4 -概要 神经发育障碍（NDD）是由分子和突触发育异常引起的。 大脑中的网络，其特征是发育行为缺陷，具有明显的社会和认知功能， 损伤在美国，大约15%的3至17岁的儿童受到NDD的影响， 包括自闭症谱系障碍（ASD）、注意力缺陷多动障碍（ADHD）、癫痫、智力障碍 残疾（ID）、听力障碍、视觉/运动障碍等。有趣的是， ASD和ID也以许多与记忆相关的缺陷为标志，例如面部身份识别，工作 记忆和情景记忆然而，基因，记忆表型和NDD之间的联系很差 明白该项目的重点是NDD风险基因IL 1 RAPL 2在人类iPSC衍生的细胞中的功能。 兴奋性神经元和ASD样和记忆行为使用一个新开发的小鼠模型。我们 假设IL 1 RAPL 2在神经发育障碍和记忆表型中起关键作用， 调节皮层兴奋性神经元的突触发育。目标1将利用人类IPSC- IL 1 RAPL 2功能丧失（LoF）的深层兴奋性神经元，以了解其在 转录组学景观，调节树突状分支和棘密度，以及神经元兴奋性 和突触传递。Aim 2将利用具有全局Il 1 rap 12 LoF的新小鼠模型来模拟 人类中的LoF突变，这将使人们能够理解它在NDD和记忆相关行为中的作用。 NIH COBRE神经发育及其障碍（CNDD）将提供一个理想的环境， 资源和核心，以及职业发展机会，使博士贝尔托成功过渡到 MUSC的独立调查员此外，拟议的研究和采用的方法， 这些数据对国家民主与发展委员会的使命和主题都很重要，而且高度相关。 Berto，用于未来的竞争R 01应用。