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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疾病的致病机制研究摘要编码细胞周期蛋白依赖性激酶样5的X连锁基因突变导致CDKL 5障碍，一种婴儿癫痫脑病与智力残疾和自闭症有共同的特征。了解CDKL 5的生物学功能在体内和CDKL5疾病的致病机制，我们以前开发和表征了一种在一个实施方案中，本发明涉及一种包含CDKL 5患者相关遗传缺陷的敲除小鼠模型。我们发现，携带CDKL 5的小鼠功能障碍发展出模仿CDKL 5障碍的关键症状的行为表型。这些老鼠也表现出在神经回路通信和多种信号转导途径的改变。由于CDKL5表达是在前脑中高度富集，我们还采用了条件性敲除方法，并消除了CDKL 5表达。不同的前脑神经元群体。我们发现，缺乏来自不同神经元细胞的CDKL 5的小鼠表现出不同的行为表型，模仿CDKL 5障碍的智力残疾样和自闭症样特征。这些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， CDKL 5障碍的智力残疾和自闭症特征的电路机制。因此我们建议开发一种创新的小鼠系，以表征CDKL 5的细胞类型特异性功能，并采取联合生物化学，遗传学，行为学和神经生理学方法来研究分子和细胞基础，在雄性和雌性中使用敲除和条件性敲除小鼠的CDKL 5病症。我们希望，揭示CDKL5功能的新方面，开发用于测试疗法的框架，并最终揭示新的治疗开发的机会，以减轻与CDKL5疾病相关的症状，以及其他相关的综合征性智力残疾和自闭症等疾病。