Evaluation of novel biomarkers of cognition in a model of sporadic developmental brain disorders and their application in efficacy testing of Ras pathway inhibitors

 描述(由申请人提供)：我们的目标是推进在智力残疾(ID)和相关障碍的小鼠模型中进行临床前翻译研究的工具和方法，如自闭症谱系障碍和癫痫。该项目的目标是优化一组方法，以预测在一种新兴的ID小鼠模型中发育性脑损伤的程度，然后使用该方法来测试FDA批准的RAS/ERK抑制剂的疗效。诊断外显子组测序已经确定SYNGAP1/Syngap1是散发性脑发育障碍患者中最常见的干扰基因之一。我们在模拟这种单基因大脑疾病的小鼠身上的研究表明，终身认知障碍是由发育中的前脑谷氨酸能神经元的孤立损伤引起的。这些神经元的损伤扰乱了发育的关键期(CP)，导致终生认知和行为中断。Syngap1编码神经元特异性的RasGAP，导致单倍体不足的致病突变增强了大脑中的RAS/ERK信号。然而，目前尚不清楚前脑谷氨酸能神经元中RAS/ERK信号的升高是否是导致该模型小鼠终身认知障碍的CP损伤的主要原因。基于我们过去的工作，确定了这种ID遗传形式下的核心神经生物学缺陷，我们开发了一个明确且可测试的治疗假说：使新生儿Syngap1突变体中升高的RAS/ERK信号正常化将保护CP免受损害，从而减轻持续性认知和行为障碍的发展。对ID小鼠模型的治疗开发是昂贵的、耗时的，并且几乎没有翻译成功。ID小鼠模型缺乏可译性的一个可能原因是缺乏高度可量化的认知功能替代测量。因此，为了最有效地评估实验性疗法在Syngap1模型小鼠中的疗效，我们还建议验证几种高度可量化的CP损伤生物标志物。由于这些小鼠的异常认知是由发育中的CP受损引起的，这些替代措施有可能在Syngap1小鼠的认知能力方面提供高度的信息。此外，这些CP损伤的候选生物标志物对人类对象具有很高的可译性，因为它们在小鼠和人类身上都很容易获得。重要的是，这些潜在的生物标记物中的一些已知在具有相似Syngap1功能丧失突变的小鼠和人类患者中给出非常相似的信号。在Syngap1小鼠身上验证高度敏感和可翻译的生物标记物，结合以CP保护为中心的独特治疗假说的有效性测试，表明本提案中概述的工作可能会促进用于开发经验疗法的工具和方法。这些进展可能会提高从小鼠ID模型转化到相应患者群体的治疗成功率。

 DESCRIPTION (provided by applicant): We aim to advance the tools and methodologies for preclinical translation studies in mouse models of intellectual disability (ID) and related disorders, such as autism spectrum disorder and epilepsy. The goal of this project is to optimize a panel of measures that predict the extent of developmental brain damage in an emerging mouse model of ID and then use this panel to test the efficacy of FDA-approved RAS/ERK inhibitors. Diagnostic exome sequencing has identified SYNGAP1/Syngap1 as one of the most commonly disrupted genes in patients with sporadic brain developmental disorders. Our studies in mice that model this monogenic brain disorder demonstrated that life-long cognitive disruptions are caused by isolated damage to developing forebrain glutamatergic neurons. Damage to these neurons disrupts a critical period (CP) of development that drives life-long cognitive and behavioral disruptions. Syngap1 encodes a neuron-specific RasGAP and pathogenic mutations leading to haploinsufficiency enhance Ras/ERK signaling in the brain. However, it is currently unknown if elevated RAS/ERK signaling within forebrain glutamatergic neurons is the primary cause of CP damage that leads to life-long cognitive disability in this mouse model. Based on our past work that identified the core neurobiological defects that underlie this genetic from of ID, we have developed a clear and testable therapeutic hypothesis: that normalizing elevated Ras/ERK signaling in neonatal Syngap1 mutants will protect the CP from damage and thus mitigate the development of persistent cognitive and behavioral disruptions. Therapeutic development in mouse models of ID is expensive, time consuming and has yielded few, if any, translational successes. One possible reason for the lack of translatability in mouse models of ID is the dearth of highly quantifiable surrogate measures of cognitive function. Thus, in order to most effectively assess the efficacy of experimental therapeutics in Syngap1 model mice, we are also proposing to validate several highly quantifiable biomarkers of CP damage. Because abnormal cognition in these mice is caused by damage to a developmental CP, these surrogate measures have the potential to be highly informative with respect to cognitive ability in Syngap1 mice. In addition, these candidate biomarkers of CP damage have a high potential for translatability to human subjects because they can be acquired easily in both mice and humans. Importantly, some of these potential biomarkers are known to give very similar signals in both mice and humans patients with similar Syngap1 loss-of-function mutations. Validation of highly sensitive and translatable biomarkers in Syngap1 mice, combined with efficacy testing of a unique therapeutic hypothesis centered on CP protection, suggests that the work outlined in this proposal could advance the tools and methodologies used to develop experiential therapeutics. These advances could increase the success rate of therapies translated from mouse ID models to corresponding patient populations.