Dysregulation of mTOR Signaling in Fragile X Syndrome

描述(由申请人提供)：脆性X综合征是最常见的智力残疾遗传性疾病，也是导致自闭症的主要遗传原因。症状在3岁时出现，通常需要在患者的一生中提供广泛的支持。据估计，在美国出生的每3000名儿童中就有一名患上脆性X综合征。与脆性X相关的认知和社会互动缺陷的有效治疗仍然是一个未得到满足的医疗需求。哺乳动物靶标雷帕霉素(MTOR)途径是细胞生长、增殖和帽依赖蛋白翻译的中心调节因子。我们最近发现，在脆性X小鼠模型中，mTOR信号过度激活，并与突触可塑性受损有关，这表明mTOR途径的失调在智能障碍的病因中具有一定的意义。我们最近与Eric Klann合作发现，在患有脆性X的人类中，mTOR信号过度激活，这突显了拟议研究的临床相关性。我们的研究发现，脆性X小鼠中脆性X智力低下蛋白(FMRP)的靶基因PI3激酶增强子(Pike)是mTOR的上游激活剂，它在FMRP和mTOR信号之间提供了功能联系。这项拟议研究的总体目标是描述脆性X综合征小鼠模型在信号、脊柱动力学、突触可塑性和认知方面的缺陷，并寻找新的治疗策略来改善这一令人衰弱的人类状况。潜在的假设是，沉默FMRP导致Pike升高和mTOR信号过度激活，这与脆性X综合征的脊柱异常、突触可塑性受损、认知和社会互动有关。目的：1.研究脆性X综合征基因与成年小鼠mTOR信号、脊髓形态发生、突触可塑性、认知和自闭症行为之间的因果关系。作为一种替代策略，我们将使用一只Fmr1小鼠来检测条件敲除Fmr1诱导mTOR信号过度激活的能力，并概括成年小鼠的脆性X表型。目的2.研究Pike升高、mTOR信号过度激活与脆性X表型之间的因果关系。目的3.作为补充策略，我们将证明mTOR信号调节失调与脆性X表型之间的因果关系。此外，我们还将检查针对mTOR的药物改善神经功能缺陷的能力。为了承担这项研究计划，我们吸引了一流的科学合作者。世界著名的突触生理学家、哈佛医学院的贝尔纳多·萨巴蒂尼将进行脊柱成像实验。突触可塑性和行为实验将与纽约大学的Eric Klann合作进行，Eric Klann是突触生理学和自闭症领域的专家。NIMH的杰奎琳·克劳利将担任行为顾问，她是自闭症小鼠模型的行为分析方面的世界知名专家。希望这项对脆性X小鼠模型中突触和回路缺陷的深入分析将改善这种人类疾病的诊断、治疗和预防。这些研究的结果将加速发现新的治疗策略，不仅对脆性X综合征，而且对其他发育障碍都具有广泛的潜力。 公共卫生相关性：脆性X综合征是最常见的精神发育迟滞的遗传性疾病，也是自闭症的主要形式。脆性X综合征与自闭症的发生率约为30%。症状在3岁时出现，通常需要在患者的一生中提供广泛的支持。据估计，在美国出生的每3000名儿童中就有一名患上脆性X综合征。与脆性X相关的认知和社会互动缺陷的有效治疗仍然是一个未得到满足的医疗需求。这项拟议的研究将检验针对mTOR信号的治疗策略拯救成年Fmr1 KO小鼠受损的突触可塑性和行为的能力。这些转化性研究将为开发新的治疗策略以改善这一严重的人类状况奠定基础。

DESCRIPTION (provided by applicant): Fragile X syndrome is the most common heritable disorder of intellectual disabilities and a leading genetic cause of autism. The onset of symptoms occurs by the age of 3, and usually requires extensive support for the lifetime of the afflicted. An estimated one in every 3000 children born in the U.S. develops Fragile X syndrome. An effective treatment for the cognitive and social interaction deficits associated with Fragile X remains an unmet medical need. The mammalian target of rapamycin (mTOR) pathway is a central regulator of cell growth, proliferation and cap-dependent protein translation. Our recent discovery that mTOR signaling is over activated in a mouse model of Fragile X and is causally related to impaired synaptic plasticity implicates dysregulation of the mTOR pathway in the etiology of intellectual disabilities. Our recent finding in collaboration with Eric Klann that mTOR signaling is over activated in humans with Fragile X underscores the clinical relevance of the proposed research. Our finding that PI3 Kinase Enhancer (PIKE), an upstream activator of mTOR and identified target of Fragile X Mental Retardation Protein (FMRP), is elevated in Fragile X mice provides a functional link between FMRP and mTOR signaling. The overall goals of the proposed research are to characterize deficits in signaling, spine dynamics, synaptic plasticity and cognition in a mouse model of Fragile X syndrome and to identify novel therapeutic strategies for amelioration of this debilitating human condition. The underlying hypothesis is that silencing of FMRP leads to elevated PIKE and over activated mTOR signaling, which are causally related to spine abnormalities, impaired synaptic plasticity, cognition and social interactions in Fragile X syndrome. Specific Aims are: Aim 1. Examine a causal relation between the gene known to cause Fragile X syndrome and impaired mTOR signaling, spine morphogenesis, synaptic plasticity, cognition and autistic behaviors in adult mice. As an alternative strategy we will use a floxed Fmr1 mouse to examine the ability of conditional knockdown of Fmr1 to induce over activated mTOR signaling and recapitulate the Fragile X phenotype in adult mice. Aim 2. Examine a causal relation between elevated PIKE, over activated mTOR signaling and the Fragile X phenotype. Aim 3. As a complementary strategy, we will document a causal relation between dysregulation of mTOR signaling and the Fragile X phenotype. In addition, we will examine the ability of drugs that target mTOR to ameliorate neurologic deficits. To undertake this research initiative, we have attracted stellar scientific collaborators. Bernardo Sabatini, Harvard Medical School, a world-renowned synaptic physiologist, will perform spine imaging experiments. Synaptic plasticity and behavioral experiments will be performed in collaboration with Eric Klann, New York University, an expert in the fields of synaptic physiology and autism. Jacqueline Crawley, NIMH, a world-renowned expert in behavioral analysis of mouse models of autism will serve as a Behavioral Advisor. It is hoped that this in-depth analysis of synaptic and circuitry defects in a mouse model of Fragile X will improve the diagnosis, treatment, and prevention of this human condition. Findings from these studies will accelerate the discovery of novel therapeutic strategies with broad potential not only for Fragile X syndrome, but other developmental disorders. PUBLIC HEALTH RELEVANCE: Fragile X syndrome is the most common heritable disorder of mental retardation and a leading form of autism. Fragile X syndrome exhibits ~30% co-occurrence with autism. The onset of symptoms occurs by the age of 3, and usually requires extensive support for the lifetime of the afflicted. An estimated one in every 3000 children born in the U.S. develops Fragile X syndrome. An effective treatment for the cognitive and social interaction deficits associated with Fragile X remains an unmet medical need. The proposed research will examine the ability of therapeutic strategies targeting mTOR signaling to rescue impaired synaptic plasticity and behavior in adult Fmr1 KO mice. These translational studies will create a foundation for generating novel therapeutic strategies to ameliorate this serious human condition.