Autonomic and Sensory Dysfunctions in FMR1 Conditions: Development, Mechanisms and Consequences

FMR1 条件下的自主神经和感觉功能障碍：发展、机制和后果

• 批准号: 10390007
• 负责人: Jane E Roberts
• 金额: $ 67.22万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-08 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10390007
• 关键词: Adaptive Behaviors; Address; Adult; Affect; Age; Anxiety; Arousal; Autonomic nervous system; Behavior; Behavioral; Biological; CGG repeat; Child; Data; Development; FMR1; FMR1 Premutation; FMRP; Female; Fragile X Premutation; Fragile X Syndrome; Functional disorder; Genetic; Genetic Variation; Heart Rate; Impairment; Individual; Infant; Inherited; Intervention; Knowledge; Learning; Length; Life; Link; Measures; Messenger RNA; Molecular Genetics; Mutation; Outcome; Pathway interactions; Phenotype; Physiological; Research; Risk; Role; Sensory; Severities; Sinus Arrhythmia; Symptoms; Time; Work; autism spectrum disorder; experience; heart function; improved; indexing; infancy; interest; male; prospective; reduce symptoms; respiratory; response; sensory stimulus; skills; social communication

PROJECT SUMMARY/ABSTRACT Despite the impairment in fragile X syndrome (FXS) and the fragile X premutation (FXpm), surprisingly little research has examined the underpinnings of these impairments. One potential factor that contributes to impairment is autonomic nervous system (ANS) dysfunction. Elevated physiological arousal, reflecting ANS dysfunction, has long been implicated as contributing to learning impairments and atypical behavior in FXS. While ANS dysfunction has been linked to impairment in both FXS and FXpm, research has not examined the presence, onset, developmental trajectory, or developmental consequences of ANS dysfunction or how molecular-genetic factors are associated. This project addresses these critical gaps with the following specific aims: (1) Identify the onset and developmental trajectory of baseline ANS dysfunction through prospective longitudinal assessment at 6, 9, 12, and 24 months in FXS (n=30 males) and FXpm (n=30; 15 males and 15 females) contrasted to typical controls (n=45; 30 males and 15 females); (2) Determine how molecular-genetic variation relates to the onset and/or developmental trajectory of ANS dysfunction in FXS and FXpm; (3) Characterize behavioral and ANS reactivity to sensory stimuli through prospective longitudinal assessment at 6, 9, 12, and 24 months in FXS and FXpm; and (4) Document the consequences of ANS dysfunction across infancy on sensory processing impairments, adaptive skills, ASD symptoms, and social communication, concurrently and at 24 months in FXS and FXpm. This work will have tremendous impact by greatly expanding information on the mechanistic underpinnings, biological pathways, and timing of symptom progression, which is essential to identify targets and timing of treatment to reduce symptom severity in FXS and FXpm. Our focus on infancy is critical, as evidence has documented that intervention provided early in life has the potential to accelerate development and improve developmental trajectories over time in a multi-dimensional manner.

项目概要/摘要 尽管脆性 X 综合征 (FXS) 和脆性 X 前突变 (FXpm) 受到损害，但令人惊讶的是， 研究探讨了这些缺陷的基础。一个潜在因素有助于 损伤是自主神经系统（ANS）功能障碍。生理唤醒升高，反映 ANS 功能障碍，长期以来一直被认为会导致 FXS 的学习障碍和异常行为。 虽然 ANS 功能障碍与 FXS 和 FXpm 损伤有关，但研究尚未检验 ANS 功能障碍的存在、发生、发育轨迹或发育后果或如何 分子遗传因素相关。该项目通过以下具体措施解决了这些关键差距 目标：（1）通过前瞻性识别基线 ANS 功能障碍的发生和发展轨迹 在 FXS（n=30 名男性）和 FXpm（n=30；15 名男性和 15 名男性）在 6、9、12 和 24 个月时进行纵向评估 女性）与典型对照（n=45；30 名男性和 15 名女性）对比； (2) 确定分子遗传学 变异与 FXS 和 FXpm 中 ANS 功能障碍的发生和/或发展轨迹有关； (3) 通过前瞻性纵向评估来表征对感觉刺激的行为和 ANS 反应 FXS 和 FXpm 的 6、9、12 和 24 个月； (4) 记录 ANS 功能障碍的后果 婴儿期的感觉处理障碍、适应技能、自闭症谱系障碍症状和社交沟通， 同时在 FXS 和 FXpm 中进行 24 个月。这项工作将通过极大地扩展而产生巨大的影响 有关机制基础、生物学途径和症状进展时间的信息， 对于确定治疗目标和时机以减轻 FXS 和 FXpm 症状严重程度至关重要。我们的重点 婴儿期的干预至关重要，因为有证据表明，生命早期提供的干预有可能 多维度加快发展、改善发展轨迹。