Pathogenic Studies of CDKL5 Disorder

CDKL5 疾病的致病研究

基本信息

批准号：
10371048
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10371048
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 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 therapeutically effective 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 疾病的致病研究抽象的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 CDKL5 疾病，这是一种婴儿癫痫病脑病与智力障碍和自闭症有共同的特征。了解CDKL5的生物学功能体内和 CDKL5 疾病的致病机制，我们之前开发并表征了包含 CDKL5 患者相关遗传缺陷的敲除小鼠模型。我们发现携带CDKL5的小鼠功能障碍会形成模仿 CDKL5 疾病关键症状的行为表型。这些小鼠也表现出缺陷神经回路通讯和多种信号转导途径的改变。鉴于 CDKL5 表达为前脑中高度富集，我们还采用了条件敲除方法并消除了前脑中的 CDKL5 表达前脑的不同神经元群。我们发现缺乏来自不同神经元细胞的 CDKL5 的小鼠表现出独特的行为表型，模仿 CDKL5 障碍的智力障碍样和自闭症样特征。这些研究结果提出了一个假设，即 CDKL5 调节细胞类型特异性信号转导途径和不同的神经 CDKL5 障碍的智力障碍和自闭症特征的回路机制。因此我们建议开发一种创新的小鼠品系来表征 CDKL5 的细胞类型特异性功能，并结合生物化学、遗传、行为和神经生理学方法来研究分子和细胞基础使用敲除和条件敲除雄性和雌性小鼠的 CDKL5 疾病。我们共同期望揭示 CDKL5 功能的新方面，开发测试疗法的框架，并最终揭示新的开发治疗方法以减轻与 CDKL5 疾病以及其他相关疾病相关的症状的机会综合症性智力障碍和自闭症等疾病。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genomic insights into MeCP2 function: A role for the maintenance of chromatin architecture.

MeCP2 功能的基因组见解：维持染色质结构的作用。

DOI：
发表时间：
2019
期刊：
影响因子：
5.7
作者：
Connolly, Daniel R;Zhou, Zhaolan
通讯作者：
Zhou, Zhaolan

Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder-related deficits.

Cdkl5 的时间操纵揭示了重要的发育后功能和可逆的 CDKL5 缺乏症相关缺陷。

DOI：
10.1172/jci143655
发表时间：
2021-10-15
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
B. Terzic;M. F. Davatolhagh;Y. Ho;Sheng Tang;Yu;Zijie Xia;Yue Cui;M. Fuccillo;Zhaolan Zhou
通讯作者：
Zhaolan Zhou

Aged heterozygous Cdkl5 mutant mice exhibit spontaneous epileptic spasms.

老年杂合 Cdk15 突变小鼠表现出自发性癫痫痉挛。

DOI：
发表时间：
2020
期刊：
影响因子：
5.3
作者：
Mulcahey, Patrick J;Tang, Sheng;Takano, Hajime;White, Alicia;Davila Portillo, Dayana R;Kane, Owen M;Marsh, Eric D;Zhou, Zhaolan;Coulter, Douglas A
通讯作者：
Coulter, Douglas A