A NOVEL TRANSLATIONAL MODEL OF AUTISUM SPECTRUM DISORDER

自闭症谱系障碍的新型翻译模型

• 批准号: 8492458
• 负责人: ANTHONY WING SANG CHAN
• 金额: $ 26.78万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8492458
• 关键词: Animal Model; Animals; Ankyrin Repeat; Award; Behavioral; Benchmarking; Characteristics; Clinical; Cognitive; Complement; Complex; Data; Dendritic Spines; Derivation procedure; Development; Developmental Process; Diagnosis; Disease; Embryo; Evaluation; Exhibits; Fertilization in Vitro; Future; Gene Targeting; Generations; Genes; Genetic; Genetic Structures; Genome; Goals; Grant; Health; Hereditary Disease; Human; Huntington Disease; Impaired cognition; Impairment; In Vitro; Incidence; Integrase; Knock-out; Lead; Macaca mulatta; Medical; Modeling; Monkeys; Mus; Mutation; Neurologic; Neurons; Oocytes; Outcome; Patients; Pattern; Phenotype; Play; Primates; Procedures; Reporting; Research; Risk Factors; Rodent; Role; Scaffolding Protein; Social Interaction; Staging; Subfamily lentivirinae; Symptoms; Technology; Therapeutic Intervention; Transgenic Model; Transgenic Organisms; Translational Research; Zinc Fingers; autism spectrum disorder; cerebral atrophy; density; disorder risk; embryonic stem cell; genetic association; genome wide association study; high risk; human disease; insight; interest; knock-down; nerve stem cell; neuropathology; nonhuman primate; novel; novel strategies; nuclease; postsynaptic; small hairpin RNA; success; synaptogenesis; therapeutic development

DESCRIPTION (provided by applicant): Recent reports have indicated a dramatic rise in the incidence of Autism spectrum disorders (ASD), which has devastating medical and financial impact worldwide. Complex genetic associations and the lack translational models that replicate the spectrum of human symptoms have significantly impeded efforts for therapeutic development and intervention. In this proposal, we will capitalize on exciting new genetic targeting technologies as well as genome-wide association studies, which have pinpointed SHANK3 as a leading disease risk factor prompting a new era in ASD research. The development of shRNA and ZFN strategies to manipulate genetic structure holds great promise for the generation of novel rhesus models with haploinsufficency or complete knockout of disease risk factors. The aims of this proposal involve two targeted approaches for the exploratory stage in the path to develop an ASD transgenic model; 1) genetic knockdown of SHANK3 with shRNA and 2) knockdown or knockout of SHANK3 with ZFN. Additionally, neural progenitor cells (NPCs) will be derived from ESCs listed above for evaluation of SHANK3 on neuronal functions. Collectively, the results yielded from this proposal will provide a critical and early benchmark for SHANK3 modulation on developmental processes and resulting neurological activity. More generally, the aims of this grant could have very broad implications for human recessive genetic diseases in addition to ASD. Notably, our team has extensive expertise necessary for successful implementation of the goals outlined above and, most importantly, have already obtained preliminary data strongly suggestive of a successful outcome. With the support of this exploratory award, we are confident that the necessary groundwork can be established such that the milestone effort to create a future ASD translational model will be achieved. Although the goals of this grant are high-risk, we strongly believe that the recent advancements in scientific technology are timely for the launching of a new approach to modeling complex human diseases.

描述（由申请人提供）：最近的报告表明自闭症谱系障碍（ASD）的发病率急剧上升，这对全世界的医疗和经济造成了毁灭性的影响。复杂的遗传关联和缺乏复制人类症状谱的转化模型极大地阻碍了治疗开发和干预的努力。在这项提案中，我们将利用令人兴奋的新基因靶向技术以及全基因组关联研究，这些研究已将 SHANK3 确定为主要的疾病风险因素，推动 ASD 研究进入新时代。操纵遗传结构的 shRNA 和 ZFN 策略的开发为产生单倍体不足或完全敲除疾病危险因素的新型恒河猴模型带来了巨大希望。该提案的目标涉及开发 ASD 转基因模型的探索阶段的两种有针对性的方法； 1) 使用 shRNA 对 SHANK3 进行基因敲除，以及 2) 使用 ZFN 对 SHANK3 进行基因敲低或基因敲除。此外，神经祖细胞 (NPC) 将从上面列出的 ESC 中提取，用于评估 SHANK3 对神经元功能的影响。总的来说，该提案产生的结果将为 SHANK3 对发育过程和由此产生的神经活动的调节提供关键的早期基准。更一般地说，这笔赠款的目的可能对除自闭症谱系障碍之外的人类隐性遗传疾病产生非常广泛的影响。值得注意的是，我们的团队拥有成功实施上述目标所需的广泛专业知识，最重要的是，我们已经获得了强烈表明成功结果的初步数据。在这一探索性奖项的支持下，我们相信能够奠定必要的基础，从而实现创建未来 ASD 转化模型的里程碑式的努力。尽管这笔赠款的目标风险很高，但我们坚信，科学技术的最新进展对于推出一种模拟复杂人类疾病的新方法来说是及时的。