MicroRNA Dysregulation in Pyschiatric Disorders and Cognitive Dysfunction

项目摘要 精神分裂症遗传病因的异质性和相应的神经系统复杂性使得 理解疾病的病理生理学和开发新的改进的治疗方法的任务， 不吉利鉴于这种复杂性，有必要确定收敛的分子和神经基板 可以作为预防或逆转疾病进展的切入点。沿着同样的思路， 通过功能丧失使蛋白质功能丧失而提供疾病保护的突变或变异 (LoF)类似于治疗剂的效果，对于设计治疗方案具有很大的希望， 恢复或预防部分或全部疾病症状。 在第一次迭代中，我们描述了22q11.2模型中microRNA的失调。 缺失，精神分裂症最强的遗传风险因素之一[Df（16）A+/-小鼠]。我们发现产后 神经元成熟的抑制剂Mirta 22/Emc 10的脑上调，代表了神经元成熟的主要转录调控。 22q11.2相关microRNA失调的影响。Df 16（A）缺陷与 LoF Mirta 22等位基因显示出对核心SCZ相关缺陷如感觉运动门控缺陷的深刻拯救， 工作和社会记忆缺陷，以及一些潜在的突触和细胞缺陷。因此 在Df（16）A+/-小鼠中观察到的几种关键疾病改变可归因于异常持续的 升高的Mirta 22水平的抑制作用。在这些发现的基础上，这次竞争性更新旨在 进一步阐明Mirta 22 LoF突变的保护性影响背后的神经底物的性质， 比较在新生儿，青少年和成人时期使用正常化Mirta 22水平的影响 小鼠模型中的条件遗传操作（包括使用新的治疗方式， 可翻译值），并确定我们的小鼠结果在人类疾病神经元中的相关性。确定 在生命周期中，当Mirta 22正常化在逆转疾病表型方面最有效时将是至关重要的。 以确定其作为治疗靶点的潜在用途。 !

PROJECT SUMMARY The heterogeneity of genetic etiology and the corresponding neural complexity of schizophrenia have rendered the task of understanding disease pathophysiology and developing new improved treatments rather inauspicious. In light of this complexity there is need to identify convergent molecular and neural substrates that can serve as entry points to prevent or reverse disease progression. Along the same lines, identification of mutations or variants that confer protection against disease by disabling protein function via loss-of-function (LoF) effects, akin to those of a therapeutic agent, hold great promise for devising therapeutic schemes to restore or prevent some or all of disease symptoms. During the first iteration of this grant, we characterized the microRNA dysregulation in a model of the 22q11.2 deletion, one of the strongest genetic risk factor for schizophrenia [Df(16)A+/- mice]. We found that postnatal brain upregulation of Mirta22/Emc10, an inhibitor of neuronal maturation, represents the major transcriptional effect of the 22q11.2-associated microRNA dysregulation. Mice where the Df16(A) deficiency is combined with a LoF Mirta22 allele show a profound rescue of core SCZ-related deficits such as sensorimotor gating deficits, working and social memory deficits, as well as several of the underlying synaptic and cellular deficits. Thus several key disease alterations observed in Df(16)A+/– mice can be attributed to the abnormally sustained inhibitory influence of elevated Mirta22 levels. Building on these findings, this competitive renewal aims to elucidate further the nature of neural substrates underlying the protective influences of Mirta22 LoF mutations, compare the effects of normalizing Mirta22 levels during neonatal, adolescent and adult time periods using conditional genetic manipulations in mouse models (including the use of new therapeutic modalities of translatable value) and determine the relevance of our mouse results in human disease neurons. Determining when during the lifespan Mirta22 normalization is most effective at reversing disease phenotypes will be crucial for determining its potential use as a therapeutic target. !