Pathogenic Studies of CDKL5 Disorder

标题 CDKL5疾病的病原学研究 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CDKL5紊乱，这是一种婴儿癫痫 脑病具有智力残疾和自闭症的共同特征。了解CDKL5的生物学功能 体内和CDKL5疾病的致病机制，我们以前开发并表征了一种 带有CDKL5患者相关基因缺陷的基因敲除小鼠模型。我们发现携带CDKL5基因的小鼠 功能障碍会发展出类似CDKL5障碍关键症状的行为表型。这些小鼠也表现出缺陷 神经回路中的通讯和多条信号转导通路的改变。假设CDKL5表达式是 在前脑高度丰富，我们还采用了条件基因敲除方法和消融CDKL5的表达 前脑的不同神经元群。我们发现，从不同神经细胞中缺乏CDKL5的小鼠表现出 明显的行为表型，模仿CDKL5障碍的智力残疾样和自闭症样特征。这些 研究结果提出了一种假设，即CDKL5调节特定细胞类型的信号转导通路和不同的神经 CDKL5障碍的智能障碍和自闭症特征的电路机制。因此，我们建议 建立一种创新的小鼠系来表征CDKL5的细胞类型特异性功能，并将其与 用生化、遗传学、行为学和神经生理学的方法来研究糖尿病的分子和细胞基础。 CDKL5基因敲除和条件性基因敲除小鼠在雄性和雌性中均存在紊乱。共同努力，我们期待着 发现CDKL5功能的新方面，开发测试疗法的框架，并最终揭示新的 治疗发展的机会，以缓解与CDKL5障碍相关的症状，以及其他相关的 综合症、智力残疾和自闭症等障碍。

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.