Pathogenic Studies of CDKL5 Disorder

CDKL5 疾病的致病研究

基本信息

批准号：
9893035
负责人：
Zhaolan Zhou
金额：
$ 53.8万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9893035
关键词：
Affect Alleles Behavior assessment Behavioral Biochemical Biochemical Genetics Biological Process Biotin Biotinylation Brain Brain region Calcium Cells Communication Cyclin-Dependent Kinases Dendritic Spines Development Diagnosis Disease Exhibits Female Functional disorder Generations Genes Genetic Glutamates Health Heterogeneity Hippocampus (Brain)Image Impaired cognition Impairment In Vitro Individual Intellectual functioning disability Knock-out Knockout Mice Lead Learning Link LoxP-flanked allele Mediating Memory Methyl-CpG-Binding Protein 2 Modeling Molecular Molecular Target Morphogenesis Mosaicism Mus Mutation Neurons Pathogenicity Patients Pharmacology Phenotype Phosphorylation Phosphotransferases Plant Roots Population Property Prosencephalon Protein-Serine-Threonine Kinases Proteins Research Seizures Signal Pathway Signal Transduction Signal Transduction Pathway Symptoms Synapses Syndrome Therapeutic Treatment Efficacy X Inactivation associated symptom autism spectrum disorder autistic autistic behaviour base behavioral phenotyping behavioral study cell type chemical genetics conditional knockout epileptic encephalopathies in vivo infancy innovation insight male motor control motor impairment mouse model neural circuit neural patterning neurophysiology novel patch clamp preclinical trial reduce symptoms segregation therapeutic development therapeutic evaluation voltage sensitive dye

项目摘要

Title Pathogenic Studies of CDKL5 Disorder Abstract Mutations in the X-linked gene encoding cyclin-dependent kinase-like 5 cause CDKL5 disorder, an infantile epileptic encephalopathy sharing features with intellectual disability and autism. To understand the biological function of CDKL5 in vivo and the pathogenic mechanisms underlying CDKL5 disorder, we previously developed and characterized a knockout mouse model incorporating a CDKL5 patient-associated genetic defect. We found that mice with CDKL5 dysfunction develop behavioral phenotypes mimicking key symptoms of CDKL5 disorder. These mice also show deficits in neural circuit communication and alterations in multiple signal transduction pathways. Given that CDKL5 expression is highly enriched in the forebrain, we also employed a conditional knockout approach and ablated CDKL5 expression in different neuronal populations of the forebrain. We found that mice lacking CDKL5 from different neuronal cells show distinct behavioral phenotypes, mimicking intellectual disability-like and autism-like features of CDKL5 disorder. These findings raise a hypothesis that CDKL5 regulates cell type-specific signal transduction pathways and different neural circuit mechanisms underlying intellectual disability and autistic features of CDKL5 disorder. We therefore propose to develop an innovative mouse line to characterize cell type-specific functions of CDKL5, and take a combined biochemical, genetic, behavioral, and neurophysiological approach to investigate the molecular and cellular basis of CDKL5 disorder using knockout and conditional knockout mice in both male and females. Together, we expect to uncover new aspects of CDKL5 function, develop a framework for testing therapeutics, and ultimately reveal new opportunities for therapeutic development to alleviate symptoms associated with CDKL5 disorder, as well as other related disorders such as syndromic intellectual disability and autism.

标题 CDKL5疾病的致病性研究抽象的编码细胞周期蛋白依赖性激酶的X连锁基因中的突变5引起CDKL5疾病，一种婴儿癫痫病脑病分享智力残疾和自闭症的特征。了解CDKL5的生物学功能体内和CDKL5疾病的致病机制，我们先前开发并表征了A 结合了CDKL5患者相关的遗传缺陷的敲除小鼠模型。我们发现带有CDKL5的小鼠功能障碍发展了模仿CDKL5疾病的关键症状的行为表型。这些老鼠还显示出赤字在神经回路的通信和多个信号转导途径的变化中。鉴于CDKL5表达是高度富集在前脑中，我们还采用了条件敲除方法和消融的CDKL5表达前脑的不同神经元种群。我们发现缺乏来自不同神经元细胞的CDKL5的小鼠显示独特的行为表型，模仿CDKL5疾病的智力障碍和类似自闭症的特征。这些发现提出了一个假设，即CDKL5调节细胞类型特异性信号转导途径和不同的神经 CDKL5疾病的智力残疾和自闭症特征的基础电路机制。因此，我们建议开发创新的鼠标线来表征CDKL5的细胞类型特异性功能，并组合生化，遗传，行为和神经生理学方法，用于研究的分子和细胞基础在男性和女性中，使用敲除和有条件的基因敲除小鼠的CDKL5疾病。在一起，我们期望发现CDKL5功能的新方面，开发一个测试治疗剂的框架，并最终揭示新的治疗发育的机会减轻与CDKL5疾病相关的症状以及其他相关的症状综合症智力残疾和自闭症等疾病。