Dysregulation of cardiovascular activity in genetic forms of autism

遗传性自闭症患者心血管活动失调

• 批准号: 2887170
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2887170
• 关键词: Dysregulation; cardiovascular; activity; genetic; forms

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by childhood onset and diagnosed based on its core symptoms of atypical social/communicative development and by the presence of repetitive behaviours and restricted interests. In addition to its cognitive and behavioural symptoms, affected individuals also have higher than expected rates of medical conditions including abnormal regulation of cardiovascular measures. Autism symptoms correlate with alterations in the central nervous system, including the prefrontal cortex and amygdala - brain regions central to processing emotions and anxiety related behaviours and which have key roles in modulating the autonomic nervous system (ANS). The primary function of the ANS is to maintain physiological homeostasis which is achieved through a dynamic balance between its sympathetic and parasympathetic subsystems. Disruption of this balance is well documented in fragile X syndrome (FXS) and is seen in at least a subset of autistic individuals. Whereas heart rate (HR) and HR variability (HRV) change in predictable patterns according to context in healthy people, fragile X and autistic individuals exhibit elevated resting HR, reduced HRV, and atypical cardiac reactivity in response to social and cognitive stressors.There are currently no effective treatments for autism. Rodent models of ASD enable studies of the causes underlying these disorders and support their preclinical research. However, a major limitation for treatment development is the lack of robust physiological signatures in these models that can be used to predict clinical efficacy. Our preliminary data indicate that rat models of two distinct genetic forms of ASD, FXS and SYNGAP1 haploinsufficiency, exhibit impairments in cognitive and exploratory behaviours that require the prefrontal cortex and amygdala. Based on these findings, we predict that ANS dysregulation will be present in our rat models and will relate to behaviours associated with fronto-amygdalar impairments. We also predict that this ANS dysregulation will be apparent in people affected by these conditions.The student will determine whether established rodent models of autism exhibit autonomic dysregulation of cardiovascular activity and test whether these medically relevant measures represent translational biomarkers, with the potential to accelerate drug development by predicting treatment response for the disorders they model through the following aims:1. The student will compare cardiac activity and its regulation in rat models of FXS (Fmr1 knockouts) and SYNGAP1 haploinsufficiency (Syngap heterozygous mutants). Because cardiac reactivity is known to vary according to context in humans, HR and its variability will be measured in these models across a range of experimental conditions that vary in the type and intensity of stressor. An implantable radio-telemetry system will be used to record multiple physiological signals from conscious, freely moving rats.2. Validation of cardiovascular regulation parameters in human data. The student will determine whether cardiovascular measures in fragile X and SYNGAP1 patient data, collected by the Stanfield lab, display similar dynamics as rodent models of these conditions.

自闭症谱系障碍 (ASD) 是一种复杂的神经发育障碍，以儿童期发病为特征，根据其非典型社交/沟通发展的核心症状以及重复行为和受限兴趣的存在进行诊断。除了认知和行为症状外，受影响的个体的健康状况也高于预期，包括心血管指标的异常调节。自闭症症状与中枢神经系统的变化相关，包括前额叶皮层和杏仁核，这些大脑区域是处理情绪和焦虑相关行为的核心区域，在调节自主神经系统 (ANS) 方面发挥着关键作用。 ANS 的主要功能是维持生理稳态，这是通过交感神经和副交感神经子系统之间的动态平衡来实现的。这种平衡的破坏在脆性 X 综合征 (FXS) 中已有充分记录，并且至少在一部分自闭症患者中可见。健康人的心率 (HR) 和心率变异性 (HRV) 根据具体情况以可预测的模式发生变化，而脆弱的 X 型个体和自闭症患者则表现出静息心率升高、HRV 降低以及对社会和认知压力源的非典型心脏反应性。目前，自闭症尚无有效的治疗方法。 ASD 啮齿动物模型能够研究这些疾病的原因并支持其临床前研究。然而，治疗开发的一个主要限制是这些模型中缺乏可用于预测临床疗效的强大生理特征。我们的初步数据表明，两种不同遗传形式的自闭症谱系障碍（FXS 和 SYNGAP1 单倍体不足）的大鼠模型表现出需要前额皮质和杏仁核的认知和探索行为障碍。基于这些发现，我们预测 ANS 失调将出现在我们的大鼠模型中，并且与额杏仁核损伤相关的行为有关。我们还预测，这种 ANS 失调在受这些疾病影响的人中会很明显。学生将确定已建立的自闭症啮齿动物模型是否表现出心血管活动的自主神经失调，并测试这些医学相关测量是否代表转化生物标志物，有可能通过通过以下目标预测对他们所建模的疾病的治疗反应来加速药物开发：1。学生将比较 FXS（Fmr1 敲除）和 SYNGAP1 单倍体不足（Syngap 杂合突变体）大鼠模型的心脏活动及其调节。由于已知心脏反应性会根据人类环境的不同而变化，因此将在这些模型中在压力源类型和强度不同的一系列实验条件下测量心率及其变异性。植入式无线电遥测系统将用于记录来自有意识、自由活动的老鼠的多种生理信号。2．人体数据中心血管调节参数的验证。学生将确定斯坦菲尔德实验室收集的脆弱 X 和 SYNGAP1 患者数据中的心血管测量是否显示出与这些条件的啮齿动物模型相似的动态。