MicroRNA Dysregulation in Pyschiatric Disorders and Cognitive Dysfunction

项目总结 精神分裂症的遗传病因的异质性和相应的神经复杂性使 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，需要确定聚合的分子和神经底物。 这可以作为预防或逆转疾病进展的切入点。按照同样的思路，确定 通过丧失功能使蛋白质功能丧失而提供对疾病的保护的突变或变体 (IOF)类似于治疗剂的作用，为设计治疗方案提供了很大的希望 恢复或预防部分或全部疾病症状。 在这项资助的第一次迭代中，我们描述了22q11.2模型中的microRNA失调。 缺失，精神分裂症最强烈的遗传风险因素之一[DF(16)A+/-小鼠]。我们发现了出生后的 大脑上调的Mirta22/Emc10，一种神经元成熟的抑制剂，代表了主要的转录 22q11.2相关的microRNA失调的影响。Df16(A)缺乏与 一个LoF Mirta22等位基因显示了对核心SCZ相关缺陷的深刻挽救，例如感觉运动门控缺陷， 工作和社会记忆缺陷，以及几个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变化可以归因于异常持续的 Mirta22水平升高的抑制性影响。在这些调查结果的基础上，此次竞争更新旨在 进一步阐明Mirta22LoF突变保护性影响的神经底物的性质， 比较新生儿、青少年和成人期间Mirta22水平正常化的效果 小鼠模型中的条件遗传操作(包括使用新的治疗方式 可翻译的价值)，并确定我们的小鼠结果与人类疾病神经元的相关性。确定 在生命周期中，当Mirta22正常化对逆转疾病最有效时，表型将是至关重要的 以确定其作为治疗靶点的潜在用途。 好了！

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. !