ISRIB as a promising therapeutic for Fragile X syndrome

ISRIB 作为脆性 X 综合征的一种有前景的治疗方法

• 批准号: 10297829
• 负责人: ROCHELLE LYNN COULSON
• 金额: $ 6.86万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-17 至 2023-07-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10297829
• 关键词: AMPA Receptors; Address; Affect; Anxiety; Array tomography; Award; Behavioral; Behavioral Assay; Biological Assay; Child; Cognition; Cognitive; Cognitive deficits; Data; Dendritic Spines; Development; Development Plans; Disease; Educational workshop; Enrollment; Environment; Etiology; FMR1; Foundations; Fragile X Syndrome; Genetic; Genetic Translation; Goals; Grant; Homeostasis; Hyperactivity; Image; Imaging Techniques; Impairment; Individual; Inherited; Intellectual functioning disability; Knock-out; Knockout Mice; Knowledge; Learning; Long-Term Depression; Manuscripts; Measures; Mediating; Membrane; Memory impairment; Molecular; Molecular Biology; Mus; Neurodevelopmental Disorder; Neurons; Outcome; Outcomes Research; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Program Development; Protein Biosynthesis; Protein Deficiency; Quality of life; Regulation; Research; Research Activity; Role; Social Behavior; Speech Delay; Structure; Surface; Synapses; Synaptic Membranes; Synaptic plasticity; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Training; Training Activity; Traumatic Brain Injury; Vertebral column; Visualization; Western Blotting; Work; Writing; autism spectrum disorder; autistic behaviour; behavior test; behavioral phenotyping; biological adaptation to stress; career; career development; cognitive performance; cognitive testing; defined contribution; improved; in vivo; inhibitor/antagonist; long term memory; model development; molecular imaging; morris water maze; mouse model; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; object recognition; programs; response; restoration; small molecule; social; social deficits; symposium; symptom treatment; targeted treatment; treatment strategy; two photon microscopy; two-photon

PROJECT SUMMARY/ABSTRACT Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by cognitive and behavioral difficulties including intellectual disability, anxiety, hyperactivity, and many other autistic behaviors. FXS is the leading genetic cause of intellectual disability, affecting millions of children worldwide, however, there is currently no cure. FXS is caused by the absence of the Fragile X Mental Retardation Protein (FMRP). This FMRP deficiency activates the integrated stress response (ISR), promoting the internalization of AMPA receptors, concomitant with deficits in dendritic spine maturation and turnover. These synaptic deficits likely underlie the cognitive deficits observed in FXS. New therapeutic strategies have immense potential for the improvement of FXS patient quality of life, however there are currently no therapies targetting the ISR. The overall objective of this proposal is to determine the efficacy of ISR modulation by the novel drug ISRIB (ISR inhibitor) in normalizing the synaptic and cognitive deficits observed in FXS. Our central hypothesis is that blocking the ISR with ISRIB will stabilize spine maturation and turnover, alleviating the behavioral and cognitive deficits observed in FXS. Utilizing an Fmr1 knockout (KO) mouse model of FXS, we will address this hypothesis in the following specific aims: 1) Determine the effect of ISRIB treatment on synaptic phenotypes in Fmr1 KO mice and 2) Determine the effect of ISRIB treatment on cognitive and social deficits in Fmr1 KO mice. We will address these aims using a combination of molecular, imaging, and behavioral techniques. We will determine the effect of ISRIB treatment on spine maturation by measuring the abundance of post-synaptic membrane-bound AMPA receptors and spine dynamics by measuring the rate of formation and elimination. The effect of ISRIB on behavioral phenotyes will be assayed by a battery of social and cognitive tests. The outcomes of this research will define the role of the ISR in the etiology of FXS and has the potential to provide a foundation for the development of new strategies for therapeutic intervention in FXS. I have developed a detailed, tailored development plan for my training during this award period including technical, scientific, and professional training activities. I will build on my strong foundation in molecular biology as well as gain technical training in array tomography, two-photon microscopy, and mouse behavioral analysis. For scientific training, I will enroll in both formal courses as well as participate in seminars at Stanford. Professionally, I will enhance my career development through workshops, conference participation, and grant and manuscript writing programs. The training environment in Dr. Mourrain’s lab and at Stanford is exceptional. In addition to my research activities, in which I will gain new technical and scientific expertise, I will participate in a variety of development programs offered at Stanford including workshops in building a successful path to an independent academic career. Dr. Mourrain is committed to my comprehensive training and together we have developed a plan that will enable me to gain increasing independence throughout the course of my training.

项目概要/摘要 脆性 X 综合征 (FXS) 是一种神经发育障碍，其特征是认知和行为障碍 困难包括智力障碍、焦虑、多动和许多其他自闭症行为。 FXS 是 智力障碍的主要遗传原因，影响着全世界数百万儿童，然而，目前 无法治愈。 FXS 是由于缺乏脆性 X 智力迟钝蛋白 (FMRP) 引起的。本次FMRP 缺乏会激活综合应激反应（ISR），促进 AMPA 受体的内化， 伴随着树突棘成熟和周转的缺陷。这些突触缺陷可能是 FXS 中观察到的认知缺陷。新的治疗策略具有改善病情的巨大潜力 FXS 患者的生活质量，但目前没有针对 ISR 的治疗方法。总体目标 该提案旨在确定新药 ISRIB（ISR 抑制剂）对 ISR 调节在正常化方面的功效 FXS 中观察到的突触和认知缺陷。我们的中心假设是用 ISRIB 阻止 ISR 将稳定脊柱的成熟和周转，减轻 FXS 中观察到的行为和认知缺陷。 利用 FXS 的 Fmr1 敲除 (KO) 小鼠模型，我们将在以下具体内容中解决这一假设 目的：1) 确定 ISRIB 治疗对 Fmr1 KO 小鼠突触表型的影响，2) 确定 ISRIB 治疗对 Fmr1 KO 小鼠认知和社交缺陷的影响。我们将通过以下方式实现这些目标： 分子、成像和行为技术的结合。我们将确定 ISRIB 治疗的效果 通过测量突触后膜结合 AMPA 受体和脊柱的丰度来影响脊柱成熟 通过测量形成和消除的速率来进行动力学分析。 ISRIB 对行为表型的影响将 通过一系列社交和认知测试进行分析。这项研究的结果将确定该机构的作用 FXS 病因中的 ISR 并有可能为新策略的开发提供基础 用于 FXS 的治疗干预。 我为我在此奖励期间的培训制定了详细的、量身定制的发展计划，包括 技术、科学和专业培训活动。我将在分子生物学方面打下坚实的基础 以及获得阵列断层扫描、双光子显微镜和小鼠行为分析方面的技术培训。 对于科学培训，我将报名参加斯坦福大学的正式课程并参加研讨会。 在专业上，我将通过研讨会、会议参与和资助来加强我的职业发展 和手稿写作程序。 Mourrain 博士的实验室和斯坦福大学的培训环境非常出色。 除了我将获得新的技术和科学专业知识的研究活动之外，我还将参加 斯坦福大学提供的各种发展计划，包括建立成功道路的研讨会 独立的学术生涯。 Mourrain 博士致力于对我进行全面的培训，我们一起 制定了一项计划，使我能够在整个培训过程中获得越来越多的独立性。