Dysregulation of mTOR Signaling in Fragile X Syndrome

脆性 X 综合征中 mTOR 信号传导失调

• 批准号: 8449928
• 负责人: R. Suzanne Zukin
• 金额: $ 7.2万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449928
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Adult; Age; Autistic Disorder; Behavior; Behavioral; Cells; Child; Cognition; Cognitive; Collaborations; Defect; Diabetes Mellitus; Diagnosis; Disease; Dominant-Negative Mutation; Drug Delivery Systems; Enhancers; Etiology; Exhibits; Foundations; Fragile X Mental Retardation Protein; Fragile X Syndrome; Genes; Genetic; Goals; Growth; Heart; Hippocampus (Brain); Human; Image; Impaired cognition; Injection of therapeutic agent; Intellectual functioning disability; Knock-out; Knockout Mice; Link; Lithium; Long-Term Depression; Malignant Neoplasms; Medical; Mental Retardation; Metabolism; Molecular; Molecular Genetics; Morphogenesis; Mus; National Institute of Mental Health; Neurologic; Neurologic Deficit; New York; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Physiology; Prevention; Protein Overexpression; Proteins; Research; Signal Transduction; Sirolimus; Small Interfering RNA; Social Interaction; Structure; Subfamily lentivirinae; Symptoms; Synapses; Synaptic plasticity; System; Testing; Therapeutic; Translations; Universities; Upstream Enhancer; Vertebral column; Wild Type Mouse; analog; autistic behaviour; cell growth; clinically relevant; developmental disease; effective therapy; genetic manipulation; improved; mTOR protein; medical schools; molecular imaging; mouse model; neural circuit; novel; novel therapeutics; public health relevance; research study; translational study; treatment strategy

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.

描述（由申请人提供）：脆弱的X综合征是最常见的遗传性智障疾病，也是自闭症的主要遗传原因。症状的发作发生在3岁时，通常需要对患者的寿命得到广泛的支持。估计在美国出生的3000名儿童中有一个患有脆弱的X综合征。与脆弱X相关的认知和社会互动缺陷的有效治疗方法仍然是未满足的医疗需求。雷帕霉素（MTOR）途径的哺乳动物靶标是细胞生长，增殖和帽依赖性蛋白质翻译的中心调节剂。我们最近发现，MTOR信号在脆弱X的小鼠模型中过度激活，并且与突触可塑性受损有因果关系，这意味着MTOR途径的失调在智力残疾的病因中。我们最近与埃里克·克兰（Eric Klann）合作的发现，在脆弱x的人类中，MTOR信号传导过度激活，这强调了拟议研究的临床相关性。我们的发现，MTOR的上游激活剂PI3激酶增强剂（Pike）在脆弱的X小鼠中升高了脆弱的X智力低下蛋白（FMRP）的靶标，它提供了FMRP和MTOR信号之间的功能联系。拟议研究的总体目标是表征脆弱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，并确定适合这种衰弱的人类状况的新型治疗策略。基本的假设是，FMRP的沉默导致派克升高和激活的MTOR信号传导，这与脊柱异常，突触可塑性受损，脆弱X综合征的认知和社交相互作用受损。具体目的是：目标1。检查已知引起易碎X综合征的基因与MTOR信号传导，脊柱形态发生，突触可塑性，认知和自闭症行为的因果关系。作为替代策略，我们将使用Floxed FMR1小鼠来检查FMR1条件敲低诱导过时激活的MTOR信号传导的能力，并概括成年小鼠中脆弱的X表型。 AIM 2。检查高架派克，激活的MTOR信号传导和脆弱的X表型之间的因果关系。目标3。作为一种互补策略，我们将记录MTOR信号失调与脆弱X表型之间的因果关系。此外，我们将研究针对MTOR改善神经系统缺陷的药物的能力。为了采取这项研究计划，我们吸引了出色的科学合作者。世界知名的突触生理学家哈佛医学院的Bernardo Sabatini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埃里克·克兰（Eric Klann）合作，纽约大学是突触生理和自闭症领域的专家。 NIMH的杰奎琳·克劳利（Jacqueline Crawley）是自闭症小鼠模型行为分析的世界知名专家，将作为行为顾问。希望对脆弱X小鼠模型中突触和电路缺陷的深入分析将改善这种人类状况的诊断，治疗和预防。这些研究的发现将加速发现新型治疗策略，不仅对脆弱的X综合征，而且对于其他发育障碍，具有广泛潜力。 公共卫生相关性：脆弱的X综合征是最常见的遗传性智障障碍和自闭症的主要形式。脆弱的X综合征与自闭症共同出现约30％。症状的发作发生在3岁时，通常需要对患者的寿命得到广泛的支持。估计在美国出生的3000名儿童中有一个患有脆弱的X综合征。与脆弱X相关的认知和社会互动缺陷的有效治疗方法仍然是未满足的医疗需求。拟议的研究将研究针对MTOR信号传导的治疗策略的能力，以挽救成人FMR1 KO小鼠的突触可塑性和行为受损。这些翻译研究将为产生新的治疗策略创造基础，以改善这种严重的人类状况。