MOLECULAR MECHANISMS UNDERLYING INTELLECTUAL DISABILITY CAUSED BY MUTATIONS IN THE CHROMATIN MODIFIER KDM5C

染色质修饰符 KDM5C 突变导致智力障碍的分子机制

基本信息

批准号：
10239753
负责人：
Julie Secombe
金额：
$ 16.67万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-23 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10239753
关键词：
Address Affect Alleles Animal Model Attenuated Biological Assay Biological Models Brain CRISPR/Cas technology Caregivers Cell Line Cell model Cells Cerebrum ChIP-seq Chromatin Chromatin Remodeling Factor Clinical Code Cognition Cognitive Cognitive deficits Complement Core Facility Defect Development Developmental Disabilities Diagnosis Disease Disease model Drosophila genus Drosophila melanogaster Epigenetic Process Etiology Fragile X Syndrome Gene Expression Gene Mutation Gene Proteins Genes Genetic Genetic Transcription Genomics Goals Histone H3 Homeostasis Homologous Gene House mice Human In Vitro Individual Induced pluripotent stem cell derived neurons Inherited Intellectual and Developmental Disabilities Research Centers Intellectual functioning disability Interdisciplinary Study Jordan Knockout Mice Knowledge Lead Link Lysine Massive Parallel Sequencing Mediating Methylation Modeling Molecular Morphology Mus Mutation Neurodevelopmental Disorder Neurologic Neurologic Deficit Neurons Organoids Pathologic Patients Pharmacology Phenotype Play Process Proteins Publications Publishing Quality of life Regulation Research Research Project Grants Ribosomal Proteins Role Source Structure Syndrome System TNFRSF5 gene Techniques Testing Transcript Translations Work analytical tool base behavioral phenotyping chromatin immunoprecipitation chromatin modification clinical database clinically relevant cohort comorbidity database of Genotypes and Phenotypes early childhood fetal fly grasp histone demethylase improved in vitro testing in vivo induced pluripotent stem cell innovation insight loss of function mutation mouse model multiple omics mutation correction neuronal circuitry novel therapeutics programs recruit ribosome profiling single-cell RNA sequencing tool transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT – RESEARCH PROJECT Mutations in the gene encoding the transcriptional regulator lysine demethylase 5C (KDM5C) are found in patients with intellectual disability (ID). While the direct link between loss of function mutations in KDM5C and ID is clear, how KDM5C functions to mediate critical neuronal processes, and therefore the consequence of mutations for mechanisms of IDD, remains unknown. The goal of this proposal is to understand the relationship between KDM5C-regulated gene expression programs and the occurrence of ID and additional comorbid features that are observed in patients. We will achieve this by bringing together a multi-disciplinary research team with expertise in complementary analytical tools and model systems to test two hypotheses. Aim 1 tests the hypothesis that the use of human iPSC-derived in vitro cell models of KDM5C-induced ID will result in the identification of clinically relevant gene expression changes and neuronal functional deficits. One key model system we will use is iPSC-derived cerebral organoids, which recapitulate structural and molecular aspects of fetal brain development and are a critical research tool used to define the underlying cause(s) of neurodevelopmental disorders. Indeed, molecular and cellular studies using in vitro organoid systems allow us to carry out studies in a human cell context that would simply not be possible in vivo. iPSCs and organoids will be generated from two sources: (1) Cells from patients with KDM5C-induced ID from a newly recruited cohort of individuals from which we are generating a genotype-phenotype database; (2) CRISPR-Cas9-mediated gene editing to generate a KDM5C null allele and a published ID allele (KDM5CA388P) that lacks histone demethylase activity using existing iPSC lines generated from typically developing controls. We will use this system to combine morphological, functional and multi-OMICS approaches to define the impact of patient- associated mutations in KDM5C. Aim 2 tests the hypothesis that the regulation of translation efficiency in neurons by the fly homolog of KDM5C is conserved in mammalian systems and that this function is important for cognition. Here we take advantage of fly and mouse animal model systems, both as discovery tools and to test hypotheses regarding possible contributors to the cognitive effects of mutations in KDM5C. Because other inherited forms of ID have altered translation and correcting this deficit has shown promise in mouse models of other ID disorders, we will test whether altered translation similarly plays a key role in a mouse model of KDM5C-induced ID. This work is significant because we will define the etiological links between mutations in human KDM5C and ID. The proposed studies are technologically innovative in the use of complementary model systems and state-of-the-art genomics techniques such as single cell transcriptomics (scRNA-seq). It is also conceptually innovative in proposing a role for translation in KDM5C-induced ID.

项目摘要/摘要 – 研究项目编码转录调节因子赖氨酸脱甲基酶 5C (KDM5C) 的基因突变存在于 KDM5C 功能突变与智力障碍 (ID) 患者之间存在直接联系。 ID 很清楚，KDM5C 如何发挥作用来介导关键的神经过程，以及因此产生的结果 IDD 机制的突变仍然未知，该提案的目的是了解 IDD 机制的突变。 KDM5C调控的基因表达程序与ID及其他疾病发生的关系我们将通过汇集多学科的力量来实现这一目标。研究团队拥有互补分析工具和模型系统的专业知识，可以测试两个假设。目标 1 检验以下假设：使用人类 iPSC 衍生的 KDM5C 诱导 ID 体外细胞模型将导致临床相关基因表达变化和神经功能缺陷的识别。我们将使用的关键模型系统是 iPSC 衍生的大脑类器官，它概括了结构和分子胎儿大脑发育的各个方面，是用于确定胎儿大脑发育的根本原因的重要研究工具事实上，使用体外类器官系统的分子和细胞研究使我们能够在人体细胞环境中进行 iPSC 和类器官不可能实现的研究。由两个来源生成：(1) 来自新招募队列的 KDM5C 诱导 ID 患者的细胞 (2) CRISPR-Cas9介导基因编辑生成 KDM5C 无效等位基因和已发表的缺少组蛋白的 ID 等位基因 (KDM5CA388P) 我们将使用从典型开发对照中生成的现有 iPSC 系的去甲基酶活性。系统结合形态学、功能和多组学方法来定义患者的影响目标 2 检验了翻译效率调节的假设。 KDM5C 的果蝇同源神经元在哺乳动物系统中是保守的，并且该功能很重要在这里，我们利用苍蝇和小鼠动物模型系统作为发现工具和测试有关 KDM5C 突变认知影响的可能因素的假设。 ID 的遗传形式具有翻译功能，并且纠正这种缺陷已在小鼠模型中显示出希望其他 ID 障碍，我们将测试改变的翻译是否同样在小鼠模型中发挥关键作用 KDM5C 诱导的 ID。这项工作意义重大，因为我们将定义人类 KDM5C 突变之间的病因学联系拟议的研究在使用互补模型系统和方面具有技术创新性。单细胞转录组学（scRNA-seq）等最先进的基因组学技术在概念上也是如此。创新性地提出了翻译在 KDM5C 诱导的 ID 中的作用。