Neurobiology and Treatment of Reading Disability in NF1

神经生物学和 NF1 阅读障碍的治疗

基本信息

批准号：
10628742
负责人：
Laurie E Cutting
金额：
$ 25.51万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2023-01-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Neurofibromatosis Type 1 (NF1), an autosomal dominant neurocutaneous syndrome with an incidence of 1:3000, is caused by a mutation in neurofibromin -- a protein that negatively impacts learning by altering RAS signaling in long term potentiation (LTP). Clinically, NF1 shows four times greater rate of learning disabilities (65%) compared to the general population (15%), including reading disability (RD), resulting in educational impairment. The negative impact on academics makes these learning disabilities, including reading disability, among the most common concerns of parents of children with NF1. In previous research (NS49096), we demonstrated that children with NF-1 with reading difficulty (NF+RD) are able to respond to standard phonologically-based reading tutoring that was originally developed to treat children in the general population with idiopathic reading disability (IRD). Of central importance to this application, another line of research in the mouse model of NF has shown that pharmacological treatment (Lovastatin) reverses learning deficits (Li et al., 2005). The assumed mechanism is that Lovastatin, an HMGCoA reductase inhibitor, upregulates RAS signaling to counteract the negative LTP effects of deficient neurofibromin, thus allowing for better memory formation during learning. This finding has stimulated translational research to assess whether Lovastatin, a medication that the American Academy of Pediatrics to endorses as safe to use in children, can reverse cognitive deficits in humans with NF1. Promising results have been found in studies that, similar to the mouse studies, measure specific cognitive domains or pair Lovastatin with training of the deficient skill. Given that (a) NF+RD benefit from reading tutoring and (b) pharmaceutical benefits appear linked to specific study designs, several next steps are needed to better understand the behavioral and neural mechanisms of cognition in NF1. Specifically, we propose a clinical trial in which we pre-treat the NF+RD children with Lovastatin for the 12 weeks prior to reading tutoring, as compared to NF+RD who receive either reading tutoring or Lovastatin; critically, like animal studies, we will target those who show impaired learning on the specific skill to be taught, i.e., NF+RD will receive reading tutoring. Both behavioral and neurobiological measures are proposed, and changes in functional and structural connectivity are expected to occur with enhanced cognition. In particular, the combination of behavioral and pharmacological intervention is hypothesized to have a synergistic effect producing greater gains in cognition and changes in neurobiology than Lovastatin or tutoring alone. In sum, our overarching goal in this next phase of our research is to capitalize on current findings to elucidate mechanisms of and best treatments for the cognitive deficits in NF1. Such approach could also have a broader applicability for better understanding human learning mechanisms in developmental disorders.

项目摘要/摘要神经纤维瘤病1型（NF1），一种常染色体显性神经皮肤综合征，发生率为 1：3000是由神经纤维蛋白突变引起的 - 一种蛋白质，通过改变RAS对学习产生负面影响长期增强（LTP）的信号传导。在临床上，NF1显示了学习障碍率的四倍（65％）与一般人群（15％）相比，包括阅读障碍（RD），导致教育损害。对学者的负面影响使这些学习障碍，包括阅读障碍， NF1儿童父母最普遍的关注之一。在先前的研究（NS49096）中，我们证明NF-1有阅读难度的儿童（NF+RD）能够对标准做出回应基于语音的阅读辅导最初是为了治疗普通人群的儿童而开发的具有特发性阅读障碍（IRD）。对此应用的重要性至关重要，这是 NF的小鼠模型表明，药理学治疗（lovastatin）会逆转学习缺陷（Li等，，， 2005）。假定的机制是HMGCOA还原酶抑制剂Lovastatin上调RAS 信号传导以抵消缺乏神经纤维蛋白的负LTP效应，从而可以更好地记忆学习过程中的形成。这一发现刺激了翻译研究，以评估lovastatin是否是美国儿科学会以安全使用的儿童使用的药物可以逆转 NF1人类的认知缺陷。在研究中发现了有希望的结果，类似于小鼠研究，测量特定的认知领域或将洛伐他汀与缺乏技能的培训相结合。鉴于（a） NF+RD受益于阅读辅导和（b）药物益处似乎与特定的研究设计有关，需要几个步骤，以更好地了解NF1认知的行为和神经机制。具体而言，我们提出了一项临床试验，在其中预处理NF+RD儿童lovastatin的12个在阅读辅导之前的几周，与接受阅读辅导或lovastatin的NF+RD相比；至关重要的是，像动物研究一样，我们将针对那些在学习的特定技能方面表现出受损的人，即NF+RD将获得阅读辅导。提出了行为和神经生物学措施，并随着认知的增强，功能和结构连通性的变化有望发生。尤其，假设行为和药理干预的结合具有协同作用与lovastatin或单独辅导相比，在认知和神经生物学的变化方面产生更大的收益。总而在下一阶段，我们的总体目标是利用当前的发现以阐明 NF1认知缺陷的机制和最佳治疗方法。这种方法也可能有一个更广泛的适用性，以更好地了解发育障碍中的人类学习机制。