A CHEMICAL LIBRARY SCREEN FOR POTENTIAL FRAGILE X THERAPEUTICA

FMR1基因中CGG重复序列长度的变异现在被认为导致至少三个 不同的疾病：卵巢早衰，脆性X相关震颤/共济失调综合征(FXTAS)，以及 典型的脆性X综合征。前两种表型与55-200的前突变等位基因相关 重复，而脆性X综合征的重复扩展超过200次。这个项目最初是 专注于FXTAS的前突变表型，成功地获得了相当大的机制洞察力 这种紊乱。对于这次更新，该项目的重点将从FXTAS转移到努力识别和 将药物和其他小分子表征为未来脆弱地区治疗试验的潜在先导化合物 X综合征。这种重点转移的原因有两个。首先，我们在FXTAS方面的大部分进展 是由于彭进博士的工作，当时他是PI实验室的一名研究员。现在，作为一个独立的教职员工 作为埃默里的一名成员，PI允许金博士将这个项目带入自己的实验室。金医生现在已经 获得了两个NIH RO1奖，以继续这一努力(R01NS05163002《rCGG介导的分子基础 神经退行性变和R01MH07609002剖析脆性X综合征的分子基础 果蝇“)。因此，这个脆弱的X中心成功地孕育了一个新的独立的、现在得到资助的研究人员 进入Fragile X字段。第二，脆弱X中心明确强调的是动物的开发和使用 测试现有药物和开发新的精神药理药物的模型。因此，我们有 将这一提议的重点转向药物开发。我们最近通过一项资金不足的努力取得了成功 筛选拯救果蝇dfmrl缺乏症的药物，并发现AMPA异常 我们认为哺乳动物海马神经元中由于Fmr1缺乏而导致的受体运输也将提供 优秀药物筛选示范体系。我们现在提出三个具体目标，以进一步发展 果蝇和海马神经元作为药物筛选方法的鉴定和表征 新化合物作为治疗脆性X综合征的潜在药物。 这项研究的结果将在两个模型中识别能够挽救FMRP缺陷表型的化合物 脆性X综合征系统。果蝇模型具有检测不同神经元的优势 拯救完整动物表型的途径和回路。海马神经元模型具有 作为哺乳动物的优势，也检测到突触强度的根本缺陷的挽救 由于不正常的AMPAR交易。总之，这些筛查应该能识别出能够 Fmr1基因敲除小鼠的拯救表型，因此为先导化合物提供了大量的 脆性X综合征药物开发的治疗潜力。

Variation in the length of the CGG-repeat in the FMR1 gene is now appreciated to result in at least three distinct disorders: premature ovarian failure, fragile X-associated tremor/ataxia syndrome (FXTAS), and the classic fragile X syndrome. The former two phenotypes are associated with premutation alleles of 55-200 repeats while fragile X syndrome is due to repeat expansion beyond 200 repeats. This project had initially focused upon the premutation phenotype of FXTAS, successful gaining considerable mechanistic insight into this disorder. For this renewal, the project's emphasis will shift from FXTAS to an effort to identify and characterize drugs and other small molecules as potential lead compounds for future therapeutic trials in fragile X syndrome. The reasons for this shift in emphasis are two-fold. First, much of our progress on FXTAS has been due to the work of Dr. Peng Jin, at the time a fellow in the Pi's laboratory. Now, as an independent faculty member at Emory, the PI has allowed Dr. Jin to take this project into his own laboratory. Dr. Jin has now obtained two NIH RO1 awards to continue this effort (R01NS05163002 "Molecular basis of rCGG-mediated neurodegeneration" and R01MH07609002 "Dissecting the molecular basis of fragile X syndrome in Drosophila"). Thus this Fragile X Center successfully seeded a new independent and now funded investigator into the fragile X field. Second, a stated emphasis for Fragile X Centers is the development and use of animal models to test existing medications and develop new psychopharmacologic medications. Accordingly, we have shifted emphasis of this proposal to drug development. We have had recent success with an unfunded effort to screen for drugs that rescue the dfmrl deficiency in Drosophila and have also discovered abnormal AMPA receptor trafficking due to Fmr1 deficiency in mammalian hippocampal neurons that we feel will also provide an outstanding model system for drug screening. We now propose three specific aims to further develop the Drosophila and hippocampal neuron assays as drug screening approaches and to identify and characterize novel compounds as potential therapeutics for fragile X syndrome. The results of this study will identify compounds able to rescue FMRP-deficient phenotypes in two model systems for fragile X syndrome. The Drosophila model has the advantage of detecting diverse neuronal pathways and circuits that rescue phenotypes in an intact animal. The hippocampal neuron model has the advantages of being mammalian and also detecting the rescue of a fundamental deficit in synaptic strength due to abnormal AMPAR trafficking. Together, these screens should identify a subset of compounds able to rescue phenotypes in the Fmr1 knockout mouse and therefore provide lead compounds with substantial therapeutic potential for drug development for fragile X syndrome.