Distinct modes of gene expression by KDM5

KDM5 的不同基因表达模式

基本信息

批准号：
10116416
负责人：
Julie Secombe
金额：
$ 33.6万
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：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2024-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116416
关键词：
Address Adult Affect Alleles Amino Acids Animal Model Architecture Behavioral Assay Binding Biological Biological Assay Biological Process Brain Caregivers Cells Cognition Cognitive Cognitive deficits Data Defect Development Disease Drosophila genus Etiology Family Gene Activation Gene Expression Gene Expression Profile Gene Expression Regulation Gene Proteins Genetic Genetic Transcription Goals Growth Human Impaired cognition Individual Intellectual functioning disability Knowledge Lead Learning Link Lysine Mediating Memory Missense Mutation Molecular Morphogenesis Mushroom Bodies Mutation Neurodevelopmental Disorder Neurons Pathway interactions Patients Phenocopy Phenotype Physiological Proteins Quality of life RNA Interference Regulator Genes Research Ribosomal Proteins Role Testing Time Transcriptional Activation Translations Work base cell type fly gene repression histone demethylase insight knock-down loss of function mutant nerve stem cell neuroblast neuron development paralogous gene prevent programs promoter recruit therapy development tool transcription factor transcriptome

项目摘要

Abstract Mutations in the lysine demethylase 5 (KDM5) family of transcriptional regulators are found in patients with intellectual disabilities (ID) that show cognitive impairment ranging from mild (IQ 50-70) to severe (IQ < 30). However, the molecular mechanisms by which KDM5 proteins impact neuronal development and function remain unknown, leaving a large knowledge gap and preventing the identification of potential treatments for affected patients. Thus, the long-term goal of our research is to define at the molecular level how KDM5 regulates gene expression patterns necessary for neuronal development and function. We will achieve this using Drosophila because it is an established model organism used to define the molecular basis of human neurodevelopmental disorders. Studies described here use a powerful combination of genetic tools, cell biological analyses and cognitive behavioral assays to dissect KDM5’s gene regulatory activities in neuronal cells at distinct stages of development. In addition to classical loss of function analyses utilizing a newly generated kdm5 null allele and cell type specific inducible RNAi-mediated knockdown assays, we have generated a set of eight fly strains, each of which harbors a mutation in Drosophila kdm5 analogous to a human ID allele. This approach is possible because all disease-associated mutations occur in evolutionarily conserved amino acids. Data generated using these tools lead us to propose the central hypothesis that KDM5 regulates the expression of genes essential for neuronal development and function, and that this is affected by missense mutations associated with intellectual disability. This hypothesis will be tested in three specific aims. The first aim addresses the role of KDM5 in adult brain function by defining the mechanism by which KDM5 activates ribosomal protein (Rp) genes, as de novo translation has an evolutionarily conserved role in learning and memory. The second aim focusses on the role of KDM5 during development by determining the mechanism by which KDM5 functions in larval neuronal stem cells (neuroblasts) to facilitate the subsequent growth and guidance of the neurons required for learning and memory. The third aim defines the temporal and spatial requirements of KDM5 for learning and memory. This work is significant because we will define new mechanisms of gene regulation by KDM5 that are critical for neuronal development and activity in addition to providing insight into the underlying causes of neurodevelopmental disorders.

抽象的在患有以下疾病的患者中发现了转录调节因子赖氨酸脱甲基酶 5 (KDM5) 家族的突变表现出认知障碍的智力障碍 (ID) 范围从轻度 (IQ 50-70) 到严重 (IQ < 30)。然而，KDM5 蛋白影响神经发育和功能的分子机制仍然存在未知，留下了巨大的知识空白，并阻碍了对受影响患者的潜在治疗方法的确定因此，我们研究的长期目标是在分子水平上确定 KDM5 如何调节基因。我们将利用果蝇来实现神经发育和功能所需的表达模式。因为它是一个已建立的模型生物体，用于定义人类神经发育的分子基础这里描述的研究使用了遗传工具、细胞生物学分析和疾病的强大组合。认知行为分析可剖析 KDM5 在不同阶段的神经元细胞中的基因调控活动除了利用新生成的 kdm5 无效等位基因进行经典功能丧失分析之外，细胞类型特异性诱导性 RNAi 介导的敲低测定，我们生成了一组八个果蝇品系，每个品系其中在果蝇 kdm5 中含有类似于人类 ID 等位基因的突变，这种方法是可能的。因为所有与疾病相关的突变都发生在进化上保守的氨基酸中。这些工具使我们提出了一个中心假设：KDM5 调节基因的表达，这些基因对于神经发育和功能，并且这受到与智力相关的错义突变的影响该假设将在三个具体目标中进行检验。第一个目标涉及 KDM5 在成人中的作用。通过定义 KDM5 激活核糖体蛋白 (Rp) 基因的机制，从头开始研究大脑功能翻译在学习和记忆中具有进化上保守的作用。通过确定 KDM5 在幼虫神经元干中发挥作用的机制来研究 KDM5 在发育过程中的作用细胞（神经母细胞）促进学习和学习所需的神经元的后续生长和指导第三个目标定义了 KDM5 对学习和记忆的时间和空间要求。这项工作意义重大，因为我们将定义 KDM5 基因调控的新机制，这对于神经发育和活动除了提供对根本原因的洞察神经发育障碍。