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: 10446957
• 负责人: Alon Goren
• 金额: $ 79万
• 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/10446957
• 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; Complex; Defect; Development; Diagnosis; Disease; Drug Screening; Early Intervention; Electrophysiology (science); Emotional; Epigenetic Process; Epilepsy; 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; Lead; 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; Pharmacology; Physiology; Play; Process; Public Health; RNA Processing; Recovery; Regulator Genes; Research; Role; SET Domain; Sensory; Severities; Structure; Symptoms; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Transcription Elongation; Translations; United States; attenuation; autism spectrum disorder; base; 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; neurotoxic; neurotoxicity; new therapeutic target; novel; pancreatic differentiation 2 protein; prevent; psychologic; racial and ethnic; relating to nervous system; 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.

项目摘要 通常伴随智力残疾（ID）的自闭症谱系障碍（ASD）是一组的一部分 通常在头两岁时诊断出的神经发育障碍。社交，情感 一生 通过一系列具有不同严重程度的使人衰弱的症状，包括刻板印象的行为特征， 癫痫发作，感官过敏性和电动机功能受损，严重干扰其每日 生活活动。 ASD是一个重要的公共卫生问题，因为它影响了54个人中的1人。它发生在所有种族中， 族裔和社会经济群体，仅在美国，每个儿童的估计总成本 在11.5美元至609亿美元之间。因此，具有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着改善某些方面 关于儿童的发展，目前尚无疾病改良治疗。尽管做出了巨大的努力，但缺乏 有效疗法可能是由于我们对分子和细胞机制的不良理解 这些条件具有非常复杂的病因。不同类型的遗传变异的数量 由于基因组测序技术的改善，与ASD相关的人不断增加。然而， 对这些遗传变化如何影响细胞和分子途径的了解仍然很少了解 脑细胞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，SETD5基因的功能丧失遗传变异，这被认为在 基因组的结构和调节神经元基因的表达。但是，很重要 SETD5控制的分子和细胞途径的知识差距以及如何与ASD相关的突变 在这个基因中，可能导致神经元功能障碍。我们和其他人开始通过 产生SETD5缺乏小鼠，并显示出神经元功能受损和类似ASD的行为的外观。 但是，小鼠模型仅限于准确地概括疾病的病理，而且还概括了 人脑发育的旷日持久。因此，它们可以导致误导性假设。补偿 对于这些局限性，我们首次使用人类诱导的多能与SETD5相关的ASD建模 干细胞（HIPSC）。从这些细胞中产生神经元，我们像以前一样概括了神经元功能障碍 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，对于保持神经元健康所必需 并连接在大脑中，可能会产生神经毒性活性。在此提案中，我们广泛地描述了 参与此过程的分子和细胞途径，并探索新的治疗靶标，以恢复或 预防SETD5突变引起的神经元功能障碍。这项研究的成功完成将 提供空前的星形胶质细胞参与ASD的看法，并有可能彻底改变其治疗。