Novel SETD5-based Molecular Mechanisms and Therapeutic Tools to Understand and Revert Neuronal Dysfunction Associated with Intellectual disability and Autism

项目摘要 自闭症谱系障碍（ASD），通常伴有智力残疾（ID），是一组 神经发育障碍，通常在头两年诊断。社会的，情感的 受影响的人的沟通能力和沟通能力在一生中都会受到严重损害， 一系列严重程度不同的衰弱症状，包括刻板的行为特征， 癫痫发作，感觉过度敏感和运动功能受损，严重干扰他们的日常生活 生活活动。ASD是一个重要的公共卫生问题，因为它影响54人中的1人。它发生在所有种族， 种族和社会经济群体，仅在美国，每个孩子每年的估计总成本 在115亿到609亿美元之间。因此，患有ID/ASD诊断儿童的家庭经历了沉重的 心理和经济负担。虽然早期干预服务可以显著改善某些方面， 儿童的发展，没有疾病修饰治疗目前可用。尽管做出了巨大努力，但缺乏 有效的治疗方法可能是由于我们对潜在的分子和细胞机制的理解不足 这些疾病的病因极其复杂。不同类型的遗传变异的数量 由于基因组测序技术的改进，与ASD相关的基因组测序不断增加。然而，在这方面， 对于这些遗传变化如何影响细胞和分子途径， 脑细胞更容易受到这些突变的影响，最终导致与ASD相关的脑功能障碍。 其中，SETD 5基因的功能丧失遗传变异，被认为在 基因组结构和调节神经元基因表达。然而，有重要的 关于SETD 5控制的分子和细胞途径以及ASD相关突变如何 会导致神经元功能障碍我们和其他人开始解决这些问题， 产生Setd 5缺陷小鼠，并显示受损的神经元功能和ASD样行为的出现。 然而，小鼠模型不仅限于准确地概括疾病病理，而且还限于准确地概括疾病病理。 人类大脑发育的漫长过程。因此，它们可能导致误导性的假设。以补偿 由于这些局限性，我们首次使用人诱导多能干细胞模型模拟了SETD 5相关的ASD。 干细胞（hiPSC）。从这些细胞产生神经元，我们概括了神经元功能障碍，如前所述。 在小鼠模型中观察到。更重要的是，我们发现了诱导这种神经元功能障碍的新机制。 特别是，我们发现星形胶质细胞，这是更丰富和必要的保持神经元健康， 并与大脑相连，可能会产生神经毒性在这个建议中，我们广泛地描述了 分子和细胞途径参与这一过程，并探索新的治疗靶点，以恢复或 预防由SETD 5突变引起的神经元功能障碍。这项研究的成功完成将 提供了星形胶质细胞参与ASD的前所未有的观点，并可能彻底改变其治疗方法。

PROJECT SUMMARY Autism spectrum disorder (ASD), which is usually accompanied of intellectual disability (ID), is part of a group of neurodevelopmental disorders that are usually diagnosed during the first two years of age. The social, emotional and communication skills of affected individuals are severely impaired throughout life and are often accompanied by a spectrum of debilitating symptoms with different degrees of severity including, stereotypic behavioral traits, epileptic episodes, sensory oversensitivity, and impaired motor functions that seriously interfere with their daily life activities. ASD is an important public health concern as it affects 1 in 54 individuals. It occurs in all racial, ethnic, and socioeconomic groups, and in the United States alone, the estimated total cost per year per children is between $11.5 and $60.9 billion. Thus, families with ID/ASD-diagnosed children experience heavy psychological and financial burdens. While early intervention services can significantly improve certain aspects of child's development, no disease-modifying treatments are currently available. Despite enormous efforts, lack of effective therapies is likely due to our poor understanding of the molecular and cellular mechanisms underlying these conditions with exceedingly complex etiology. The number of different types of genetic variations associated with ASD keeps increasing thanks to the improvement in genomic sequencing technology. However, there is still little understanding of how these genetic changes impact cellular and molecular pathways or which brain cell are more affected by these mutations that ultimately result in brain dysfunction associated with ASD. Among them, loss-of-function genetic variations in the SETD5 gene, which is believe to play an important role in the structure of the genome and in regulating expression of neuronal genes. However, there are important knowledge gaps on the molecular and cellular pathways controlled by SETD5 and how ASD-related mutations in this gene could contribute to neuronal dysfunction. We and others started to address these questions by generating Setd5 deficient mice and showed impaired neuronal function and appearance of ASD-like behaviors. However, mouse models are limited to accurately recapitulate not only disease pathologies but also the protracted process of human brain development. Thus, they can lead to misleading hypothesis. To compensate for these limitations, we have modeled for the first time SETD5-related ASD using human induced pluripotent stem cells (hiPSC). Generating neurons from these cells we recapitulated neuronal dysfunction as previously observed in mice models. More importantly, we uncovered new mechanisms inducing this neuronal dysfunction. In particular, we found that astrocytes, which are more abundant and necessary for keeping neurons healthy and connected in the brain, might produce neurotoxic activity. In this proposal, we extensively characterize the molecular and cellular pathways involved in this process and explore novel therapeutic targets to revert or prevent neuronal dysfunction induced by SETD5 mutations. The successful completion of this research will provide an unprecedented view of astrocyte involvement in ASD and potentially revolutionize its treatment.