Determining whether metabolic and mitochondrial pathophysiology are a common feature of three distinct genetic models of ASD

确定代谢和线粒体病理生理学是否是自闭症谱系障碍（ASD）三种不同遗传模型的共同特征

• 批准号: 10533812
• 负责人: THOMAS A JONGENS
• 金额: $ 19.93万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-03 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533812
• 关键词: Address; Affect; Animal Model; Behavior; Behavioral; Behavioral Symptoms; Biochemical; Cell physiology; Clinic; Clinical; Clinical Research; Cognition; Cognitive; Cyclic AMP; Defect; Disease; Drosophila genus; FMR1; Fragile X Syndrome; Functional disorder; Genes; Genetic; Genetic Models; Goals; Hand; Heritability; Homologous Gene; Impaired cognition; Individual; Insulin; Intellectual functioning disability; Knowledge; Language; Link; Memory; Metabolic; Metabolic dysfunction; Metabolism; Mitochondria; Modeling; Molecular; Molecular Probes; Nervous System; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurofibromatosis 1; PIK3CG gene; Pathogenesis; Patients; Phase II Clinical Trials; Phenotype; Pre-Clinical Model; Property; Proteins; Regulation; Reporting; Research Personnel; Signal Pathway; Signal Transduction; Stimulation of Cell Proliferation; Syndrome; Technology; Translating; associated symptom; autism spectrum disorder; behavioral impairment; circadian; dFMR1 gene; efficacy evaluation; expectation; fly; gene function; genetic risk factor; genome sequencing; genomic locus; improved; insulin signaling; loss of function; loss of function mutation; mitochondrial dysfunction; mouse model; mutant; null mutation; pleiotropism; pre-clinical

In the last twenty years hundreds of potential genetic risk factors for autism have been identified. The mechanisms by which these genetic loci are linked to autism however are poorly understood, but many clues are coming from the use of animal models. Fragile X Syndrome (FXS), neurofibromatosis type 1 (NF1), and deletions in the Neurexin 1 gene (NRX1) are three such prevalent monogenic forms of autism, that are caused by loss of FMR1, NF1, and NRX1 gene function, respectively. Recent clinical findings suggest that, in addition to the well known behavioral and cognitive symptoms associated with these diseases, affected individuals also present with a variety of systemic phenotypes and metabolic abnormalities, likely due to the pleiotropic effects of the FMR1, NF1, and NRX1 genes. These findings come in hand with recent evidence implicating mitochondrial dysfunction in the pathogenesis of intellectual disability related syndromes and autism. Our prior studies, as well as that of others, have uncovered that Drosophila and mammalian models of FXS and NF1 have robust cellular signaling cascade defects, including decreased cAMP and increased insulin/PI3K signaling. The importance of these signaling defects is shown by the fact that our lab and others, have demonstrated that increasing cAMP levels is sufficient to restore behavior and cognition in Drosophila and murine models of FXS and NF1. We have also shown that reduction of insulin signaling in the Drosophila model of FXS ameliorates circadian and memory phenotypes. In our proposed studies we explore mitochondrial function in three Drosophila models of monogenetic forms of autism to determine if mitochondrial defects exist and if so, define commonalities and differences amongst them. We will also explore the impact that identified signaling pathway defects have on mitochondrial function in the NF1 and FXS models to determine if mitochondrial activity may be impacted by these signaling defects and thus contribute to the phenotypes displayed by these models.

在过去的二十年里，已经确定了数百种可能导致自闭症的遗传风险因素。这个 然而，这些遗传位点与自闭症相关的机制却知之甚少，但有许多线索 都来自于动物模型的使用。脆性X综合征(FXS)、1型神经纤维瘤病(NF1)和 NRX1基因的缺失是三种常见的自闭症的单基因形式，由 FMR1、NF1和NRX1基因功能缺失。最近的临床研究结果表明，此外 与这些疾病相关的众所周知的行为和认知症状，受影响的个人也 存在各种全身表型和代谢异常，可能是由于多效性作用 FMR1、NF1和NRX1基因。这些发现与最近的证据相一致，表明线粒体 智力障碍相关综合征和自闭症发病机制的障碍。 我们之前的研究以及其他人的研究已经发现，果蝇和哺乳动物模型 FXS和NF1具有强大的细胞信号级联缺陷，包括cAMP减少和增加 胰岛素/PI3K信号转导。这些信号缺陷的重要性体现在以下事实上：我们的实验室和其他实验室， 已经证明，增加cAMP水平足以恢复果蝇的行为和认知，并 FXS和NF1小鼠模型。我们还表明，在果蝇模型中胰岛素信号的减少 改善昼夜节律和记忆表型。 在我们提出的研究中，我们探索了三种单基因发育果蝇模型的线粒体功能 确定是否存在线粒体缺陷的自闭症形式，如果存在，定义共性和差异 在他们当中。我们还将探索已识别的信号通路缺陷对线粒体的影响 在NF1和FXS模型中发挥作用，以确定线粒体活性是否可能受到这些信号的影响 缺陷，从而促成了这些模型所显示的表型。