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

基于 SETD5 的新型分子机制和治疗工具来理解和恢复与智力障碍和自闭症相关的神经元功能障碍

• 批准号: 10585929
• 负责人: Alon Goren
• 金额: $ 78.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-05 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585929
• 关键词: 2 year old; ATAC-seq; Acute; Address; Affect; Antisense Oligonucleotides; Appearance; Astrocytes; Attenuated; Automobile Driving; Behavior; Behavioral; Binding; Biochemical; Biological Assay; Brain; CRISPR-mediated transcriptional activation; CRISPR/Cas technology; Catalogs; Cells; ChIP-seq; Child; Child Development; Chromatin; Clinical; Communication; Compensation; Complex; Defect; Development; Diagnosis; Disease; Drug Screening; Early Intervention; Electrophysiology (science); Emotional; Epigenetic Process; Epilepsy; Ethnic Origin; Etiology; Failure; Family; Financial Hardship; Functional disorder; Gene Targeting; Genes; Genetic; Genetic Variation; Genome; Genomics; Goals; Heterogeneity; Histones; Homeostasis; Human; Human Development; IL6 gene; Impaired cognition; Impairment; In Vitro; Individual; Intellectual functioning disability; Interpersonal Relations; Janus kinase; Knowledge; Life; Link; Lysine; Mediating; Methods; Methyltransferase; Modeling; Molecular; Motor; Mus; Mutate; Mutation; NCOR1 gene; Neurodevelopmental Disorder; Neuronal Dysfunction; Neurons; Nuclear Pore Complex; Optics; Outcome; Pathology; Pathway interactions; Physiology; Play; Process; Public Health; RNA Processing; Race; Recovery; Regulator Genes; Research; Role; SET Domain; Sensory; Severities; Stereotyping; Structure; Symptoms; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Transcription Elongation; Translations; United States; Visualization; attenuation; autism spectrum disorder; brain cell; brain dysfunction; chromatin remodeling; cost; design; disabling symptom; disorder risk; effective therapy; experience; genetic variant; genome editing; genomic tools; global run on sequencing; improved; induced pluripotent stem cell; kinase inhibitor; loss of function; motor impairment; mouse model; multiple omics; neural; neurotoxic; neurotoxicity; new therapeutic target; novel; pancreatic differentiation 2 protein; pharmacologic; prevent; psychologic; risk variant; service intervention; single-cell RNA sequencing; skills; social; socioeconomics; synaptogenesis; therapeutic target; tool; trait

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.

项目概要 自闭症谱系障碍 (ASD) 通常伴有智力障碍 (ID)，是一组 通常在头两岁时诊断出的神经发育障碍。社会性、情感性 受影响个体的沟通能力在一生中都会受到严重损害，并且经常伴随 一系列不同严重程度的衰弱症状，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，因为每 54 个人中就有 1 人受到影响。它发生在所有种族中， 种族和社会经济群体，仅在美国，每个儿童每年的估计总成本 介于 11.5 至 609 亿美元之间。因此，患有智力障碍/自闭症谱系障碍 (ID/ASD) 诊断儿童的家庭承受着沉重的负担 心理和经济负担。虽然早期干预服务可以显着改善某些方面 儿童发育的影响，目前尚无缓解疾病的治疗方法。尽管付出了巨大的努力，但仍缺乏 有效疗法的出现可能是由于我们对潜在的分子和细胞机制了解不足 这些病症的病因极其复杂。不同类型遗传变异的数量 由于基因组测序技术的进步，与 ASD 相关的疾病不断增加。然而， 对于这些基因变化如何影响细胞和分子途径或哪些基因变化仍然知之甚少。 脑细胞更容易受到这些突变的影响，最终导致与自闭症谱系障碍相关的脑功能障碍。 其中，SETD5基因的功能丧失遗传变异被认为在 基因组的结构和神经元基因表达的调节。然而，有重要的 SETD5 控制的分子和细胞途径以及 ASD 相关突变的知识差距 该基因可能导致神经元功能障碍。我们和其他人开始通过以下方式解决这些问题 产生 Setd5 缺陷的小鼠并表现出神经元功能受损和 ASD 样行为的出现。 然而，小鼠模型不仅限于准确重现疾病病理学，而且还无法准确重现 人类大脑发育的漫长过程。因此，它们可能会导致误导性的假设。为了补偿 针对这些限制，我们首次使用人类诱导多能模型来模拟 SETD5 相关的自闭症谱系障碍 (ASD) 干细胞（hiPSC）。从这些细胞生成神经元，我们如前所述重现了神经元功能障碍 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更丰富，也是保持神经元健康所必需的 并连接到大脑中，可能会产生神经毒性活动。在本提案中，我们广泛描述了 参与这一过程的分子和细胞途径，并探索新的治疗靶点以恢复或 预防 SETD5 突变引起的神经元功能障碍。本研究的顺利完成将 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。