Dysregulation of mTOR Signaling in Fragile X Syndrome

描述（申请人提供）：脆性X综合征是智力残疾中最常见的遗传性疾病，也是自闭症的主要遗传原因。症状在3岁时出现，通常需要患者一生的广泛支持。据估计，在美国出生的每3000名儿童中就有一名患有脆性X综合征。与脆性X染色体相关的认知和社会互动缺陷的有效治疗仍然是一个未满足的医疗需求。哺乳动物雷帕霉素靶蛋白（mTOR）通路是细胞生长、增殖和帽依赖性蛋白翻译的中心调节因子。我们最近发现，在脆性X染色体小鼠模型中，mTOR信号传导过度激活，并且与受损的突触可塑性有因果关系，这暗示了智力残疾病因学中mTOR通路的失调。我们最近与Eric Klann合作发现，mTOR信号在脆性X患者中过度激活，这强调了拟议研究的临床相关性。我们发现，PI3激酶增强子（PIKE），mTOR的上游激活剂和鉴定的脆性X智力迟钝蛋白（FMRP）的靶点，在脆性X小鼠中升高，提供了FMRP和mTOR信号传导之间的功能联系。拟议研究的总体目标是表征脆性X综合征小鼠模型中信号传导、脊柱动力学、突触可塑性和认知的缺陷，并确定改善这种使人衰弱的疾病的新治疗策略。潜在的假设是FMRP的沉默导致PIKE升高和mTOR信号过度激活，这与脆性X综合征中的脊柱异常、突触可塑性受损、认知和社会互动有因果关系。具体目标是：目标1。检查已知导致脆性X综合征的基因与成年小鼠中受损的mTOR信号传导、脊柱形态发生、突触可塑性、认知和自闭症行为之间的因果关系。作为替代策略，我们将使用floxed Fmr1小鼠来检查Fmr1的条件性敲低诱导过度活化mTOR信号传导并在成年小鼠中重现脆性X表型的能力。目标二。检查PIKE升高、mTOR信号过度激活和脆性X表型之间的因果关系。目标3：作为一种补充策略，我们将记录mTOR信号转导失调和脆性X表型之间的因果关系。此外，我们将研究靶向mTOR的药物改善神经功能缺损的能力。为了开展这项研究计划，我们吸引了一流的科学合作者。贝尔纳多·萨巴蒂尼，哈佛医学院，世界著名的突触生理学家，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，他是突触生理学和自闭症领域的专家。杰奎琳·克劳利，NIMH，一位世界知名的自闭症小鼠模型行为分析专家将担任行为顾问。希望这种对脆性X染色体小鼠模型中突触和电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不仅对脆性X综合征而且对其他发育障碍具有广泛潜力的新治疗策略。

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.