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The Role of DEPDC5 in Epileptogenesis and Brain Malformations

DEPDC5 在癫痫发生和脑畸形中的作用

基本信息

批准号：
9899339
负责人：
Christopher Joseph Yuskaitis
金额：
$ 18.73万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899339
关键词：
Address Adult Affect Amino Acids Amino Acids Activation Architecture Award Boston Brain Cell model Cessation of life Child Chronic Complex Cortical Malformation Development Electrocardiogram Electroencephalography Embryo Epilepsy Epileptogenesis Exhibits FRAP1 gene Focal Seizure Foundations Funding Genes Goals Growth Factor Human Hyperactive behavior In Vitro Injections Knock-out Knockout Mice Knowledge Lead Light Lysosomes Measures Mediating Mediator of activation protein Mentorship Metabolism Modeling Molecular Motor Cortex Mus Neonatal Neurons Nutrient Pathogenicity Pathway interactions Patients Pediatric Hospitals Pharmaceutical Preparations Phenotype Physicians Play Population Precision therapeutics Predisposition Proteins Regulation Reporting Research Research Project Grants Resources Role Scientist Seizures Signal Pathway Signal Transduction Sirolimus Solid Structure Synapsins Telemetry Testing Therapeutic Therapeutic Intervention Transgenes Tuberous sclerosis protein complex Variant autism spectrum disorder brain malformation career detection of nutrient experimental study genetic variant in vitro Model in vivo in vivo Model inhibitor/antagonist insight medical schools mortality mouse model neurogenetics neuron loss neuronal cell body neurotransmission novel postnatal pre-clinical premature preservation prevent response therapeutic evaluation trafficking

项目摘要

PROJECT SUMMARY/ABSTRACT Epilepsy affects approximately 1% of the population and one in 200 children. Disruption in many epilepsy-related genes alters signaling mediated by the mechanistic target of rapamycin (mTOR) pathway, which has been implicated not only in epilepsy but also in brain malformations and autism. The mTOR complex 1 (mTORC1) coordinates cellular metabolism through growth factors and amino acids that operate on two converging parallel pathways. Growth factor activation of mTORC1 and regulation by the tuberous sclerosis complex (TSC) have demonstrated roles in the regulation of brain development and neuronal activity. In contrast, amino acid activation of mTORC1 and regulation by DEP domain-containing 5 (DEPDC5) are yet to be rigorously studied in the brain. Genetic variants in the DEPDC5 gene have been found in patients with epilepsy and structural alterations in brain development (i.e. malformations of cortical development) suggesting that its protein product DEPDC5 plays an important role in the brain. Several questions remain about the mechanisms by which DEPDC5 regulates mTORC1 in neurons and how this impacts brain development, including whether DEPDC5 regulates amino acid mediated mTORC1 signaling in neurons. Answering these questions may open the possibility of therapeutically modulating nutrient signaling as a treatment for epilepsy. This project will establish in vivo and in vitro models of Depdc5 deficiency and address a crucial knowledge gap by defining the impact of DEPDC5 loss on neuronal signaling and brain development. Recently, I generated a mouse mode with brain-specific Depdc5 loss that has several features similar to patients with DEPDC5-related epilepsy (Yuskaitis et al., Neurobiol Dis 2018). These mice have seizures, abnormal neurons with hyperactive mTORC1 activity, and die prematurely in adulthood of an unknown cause. The first aim of the proposed project is to determine 1) whether the brain-specific Depdc5 knockout mice die prematurely from seizures, and 2) whether the drug rapamycin (an mTORC1 inhibitor) can prolong survival and stop seizures of these mice. Second, I will investigate whether DEPDC5 loss affects nutrient signaling in neurons. Third, I will establish a novel mouse model to determine whether the timing of Depdc5 loss impacts epilepsy and brain development independently. The proposed research will provide essential insights into the mechanisms underlying brain development and identify potential treatments for epilepsy. My career goal is to become an independent neurogenetics scientist with a focus on using cellular and mouse models to discern the fundamental mechanisms underlying brain development and epileptogenesis. My proposal combines a focused research project, exceptional mentorship, and rich institutional resources at Boston Children's Hospital and Harvard Medical School, which provide a solid foundation for my transition into an independently funded physician-scientist during this award.

项目概要/摘要大约 1% 的人口和每 200 名儿童中就有 1 人患有癫痫症。许多方面受到干扰癫痫相关基因改变雷帕霉素靶点（mTOR）通路介导的信号传导，这不仅与癫痫有关，还与大脑畸形和自闭症有关。 mTOR 复合物 1 (mTORC1) 通过作用于两个细胞的生长因子和氨基酸协调细胞代谢汇聚平行路径。 mTORC1 的生长因子激活和结节性硬化症的调节复合物（TSC）已被证明在调节大脑发育和神经元活动中发挥作用。在相比之下，mTORC1 的氨基酸激活和包含 DEP 结构域的 5 (DEPDC5) 的调节尚待研究。在大脑中进行严格的研究。在患有以下疾病的患者中发现了 DEPDC5 基因的遗传变异癫痫和大脑发育的结构改变（即皮质发育畸形）表明其蛋白质产物DEPDC5在大脑中发挥着重要作用。关于该协议还有几个问题 DEPDC5 调节神经元中 mTORC1 的机制以及这如何影响大脑发育，包括 DEPDC5 是否调节神经元中氨基酸介导的 mTORC1 信号传导。回答这些这些问题可能会开启通过调节营养信号来治疗癫痫的可能性。该项目将建立 Depdc5 缺陷的体内和体外模型，并解决一个关键问题通过定义 DEPDC5 丢失对神经元信号传导和大脑发育的影响来确定知识差距。最近，我生成了一种具有大脑特异性 Depdc5 损失的小鼠模式，其具有几个类似的功能 DEPDC5 相关癫痫患者（Yuskaitis 等人，Neurobiol Dis 2018）。这些小鼠出现癫痫发作， mTORC1 活性过度活跃的异常神经元，并在成年后因不明原因过早死亡。该项目的首要目标是确定 1) 大脑特异性 Depdc5 敲除小鼠是否死亡过早地避免癫痫发作，以及 2) 药物雷帕霉素（一种 mTORC1 抑制剂）是否可以延长生存期并停止这些小鼠的癫痫发作。其次，我将研究 DEPDC5 丢失是否影响营养信号神经元。第三，我将建立一个新的小鼠模型来确定Depdc5丢失的时间是否会产生影响癫痫和大脑发育独立。拟议的研究将为以下方面提供重要的见解：大脑发育的机制并确定癫痫的潜在治疗方法。我的职业目标是成为一名独立的神经遗传学科学家，专注于利用细胞和小鼠模型来辨别大脑发育和癫痫发生的基本机制。我的提案结合了重点研究项目、卓越的指导和丰富的机构资源波士顿儿童医院和哈佛医学院为我的过渡提供了坚实的基础在此奖项期间获得独立资助的医师科学家。