Signaling Mechanisms Underlying Epilepsy and Autism Cormorbidity

癫痫和自闭症疾病背后的信号机制

• 批准号: 8878666
• 负责人: JOAQUIN N LUGO
• 金额: $ 41.55万
• 依托单位: BAYLOR UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2018-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8878666
• 关键词: Adult; Affect; Animal Model; Animals; Attention; Autistic Disorder; Behavior; Behavioral; Benchmarking; Biomedical Research; Cell Adhesion; Child; Childhood; Cognitive deficits; Comorbidity; DNA Sequence Alteration; Data; Development; Developmental Disabilities; Disabled Persons; Epilepsy; Flurothyl; Fostering; Goals; Health; Hereditary Disease; Hippocampus (Brain); Human; Imaging Techniques; Immunohistochemistry; Impaired cognition; Individual; International; Investigation; Learning; Learning Disabilities; Learning Disorders; Life; Link; Long-Term Effects; Manuscripts; Mediating; Mediator of activation protein; Medical; Memory; Memory impairment; Mental Retardation; Mission; Modeling; Molecular; Molecular Analysis; Mus; Mutation; National Institute of Neurological Disorders and Stroke; Outcome; PI3K/AKT; PTEN gene; Pathway interactions; Peer Review; Pharmacological Treatment; Play; Potassium Channel; Preparation; Proteins; Psyche structure; Public Health; Publications; Research; Role; Scaffolding Protein; Science; Seizures; Severities; Signal Pathway; Signal Transduction; Signaling Protein; Sirolimus; Social Behavior; Status Epilepticus; Synapses; TSC1 gene; TSC2 gene; Techniques; Up-Regulation; Western Blotting; Work; base; behavioral outcome; communication behavior; graduate student; handicapping condition; improved; inhibitor/antagonist; innovation; insight; journal article; knowledge base; mTOR protein; meetings; molecular imaging; mouse model; postsynaptic; presynaptic; prevent; public health relevance; research study; social; social learning; therapeutic target; undergraduate student

 DESCRIPTION (provided by applicant): One of the most significant consequences of developmental epilepsy is the long-term effect on behavior in children. Children who have epilepsy early in life have a higher rate of mental retardation, learning disabilities, and share a high comorbidity with autism. Mutations in the mammalian target of rapamycin (mTOR) signaling pathway are associated with higher rate of epilepsy, autism, and cognitive impairments. Therefore, abnormal activation of the mTOR signaling pathway may be an important mechanism underlying the behavioral outcomes of developmental epilepsy. The long-term goal is to identify the molecular correlates for the social behavior and other behavioral abnormalities that occur after early-life seizures and to develop therapeutic targets to treat thes behavioral abnormalities. This hypothesis has been formulated on pilot data that show a link between early-life seizures and the development of social behavior deficits in a mouse model of epilepsy. These mice demonstrate deficits in learning and memory and have upregulation of mTOR pathway signaling in the hippocampus. Guided by the pilot data presented in this proposal and the hypothesis that seizures induced at different developmental periods induce autistic-like behavioral outcomes and correlated changes in the mTOR signaling pathway, this proposal will involve the following two aims: 1) Identify the autism-like behavioral deficits and deficits in learning and memory in mice that had status epilepticus or multiple seizures during early-life or in adulthood. 2) Identify the mTOR signaling proteins and synaptic proteins that are altered in mice that had status epilepticus or multiple seizures during early-life or in adulthood. The approach is innovative because it seeks to examine the wider behavioral spectrum of the behavioral consequences due to seizures using two seizure models. The research proposed will also examine a pathway that has shown great promise to reduce/eliminate seizures but has received less attention in terms of behavioral consequences after seizures. We will also examine the pre-and postsynaptic changes that occur with aberrant mTOR activation. The proposed research is significant because it will be the first step in a continuum of research that will systematically identify the autistic- like behavioral changes and alterations in the mTOR signaling pathway that occur after seizures. It is the ultimate goal of this proposal to provide possible pharmacological treatments for the behavioral and molecular alterations in individuals with autism and epilepsy. Furthermore, the work outlined in this proposal will provide research opportunities for undergraduates to engage in hands-on biomedical research that will provide insights into the relationship between epilepsy and autism.

 描述（由申请人提供）：发育性癫痫最重要的后果之一是对儿童行为的长期影响。在生命早期患有癫痫的儿童有更高的智力迟钝，学习障碍的发生率， 与自闭症有高度共病性哺乳动物雷帕霉素靶蛋白（mTOR）信号通路的突变与癫痫、自闭症和认知障碍的发生率较高相关。因此，mTOR信号通路的异常激活可能是发育性癫痫行为结局的重要机制。长期目标是确定与早期癫痫发作后发生的社会行为和其他行为异常相关的分子，并开发治疗这些行为异常的治疗靶点。这一假设是根据试验数据制定的，这些数据显示了癫痫小鼠模型中早期癫痫发作与社会行为缺陷发展之间的联系。这些小鼠表现出学习和记忆缺陷，并且海马体中mTOR通路信号传导上调。在本提案中提出的初步数据以及在不同发育时期诱导的癫痫发作诱导自闭症样行为结果和mTOR信号通路相关变化的假设的指导下，本提案将涉及以下两个目标：1）鉴定在早期或成年期患有癫痫持续状态或多次癫痫发作的小鼠中的自闭症样行为缺陷和学习记忆缺陷。2)鉴定在早期或成年期癫痫持续状态或多次癫痫发作的小鼠中改变的mTOR信号蛋白和突触蛋白。 该方法是创新的，因为它试图研究更广泛的行为谱的行为后果，由于癫痫发作使用两种癫痫发作模型。拟议的研究还将研究一种途径，这种途径在减少/消除癫痫发作方面表现出很大的希望，但在癫痫发作后的行为后果方面受到的关注较少。我们还将研究异常mTOR激活时发生的突触前和突触后变化。这项拟议中的研究意义重大，因为它将是一系列研究的第一步，这些研究将系统地识别癫痫发作后发生的自闭症样行为变化和mTOR信号通路的改变。这是该提案的最终目标，为自闭症和癫痫患者的行为和分子改变提供可能的药物治疗。此外，本提案中概述的工作将为本科生提供研究机会，让他们从事动手的生物医学研究，从而深入了解癫痫和自闭症之间的关系。