Pre-clinical evaluation of oxytocin for ASD treatment discovery

催产素用于 ASD 治疗发现的临床前评估

基本信息

批准号：
8824009
负责人：
Melissa Dawn Bauman
金额：
$ 24.49万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8824009
关键词：
4 year old Adolescent Adult Aggressive behavior Animal Model Animals Anxiety Attention Autistic Disorder Beds Behavior Behavior Therapy Behavioral Behavioral Assay Biological Biological Assay Blood Banks Brain Breathing Cerebrospinal Fluid Child Clinical Clinical Trials Communication Complex Data Development Emotional Environment Evaluation Eye Face Family Frequencies Future Genes Genetic Health Human Individual Intervention Laboratories Lead Life Macaca Macaca mulatta Measures Medicine Mental Depression Methods Modeling Monkeys Mus Neuroanatomy Neurosciences Research Neurosecretory Systems Nose Outcome Measure Oxytocin Patients Peripheral Pharmacological Treatment Phenotype Physiology Play Population Primates Protocols documentation Quality of life Reporting Research Rodent Model Safety Sampling Signal Transduction Social Behavior Social Functioning Societies Symptoms System Testing Time Translations Treatment Efficacy Variant autism spectrum disorder base drug discovery high throughput screening improved indexing innovation insight mouse model nonhuman primate novel pre-clinical programs public health relevance repository research clinical testing social social communication therapy design trait week trial

项目摘要

DESCRIPTION (provided by applicant): While intensive behavioral intervention delivered early in life improves social functioning for some children with autism spectrum disorder (ASD), current pharmacological treatments are limited to targeting only peripheral symptoms such as aggression, anxiety, and depression. Novel pharmacological interventions specifically targeting social behavior delivered in parallel with behavioral intervention holds the promise of improving quality of life for many individuals with ASD. Development of pro-social pharmacological treatments will depend upon the successful translation of basic neuroscience research into safe and effective medicines and will require the use of sophisticated animal models. While current ASD drug discovery efforts have relied primarily upon mouse models to evaluate compound efficacy, pharmacological interventions targeting the complex social and communication deficits of ASD may ultimately require the use of an animal model more closely related to humans. Rhesus monkeys are considered the biomedical model species of choice due to their resemblance in human physiology, neuroanatomy and behavior. Although there are currently no validated nonhuman primate models of ASD, we believe that natural variation in sociability of rhesus monkeys provides a novel model to evaluate the efficacy of pro-social pharmacological treatments. We have established behavioral phenotyping protocols to identify low-social and high-social juvenile monkeys in their natal field cages and to reliably quantify changes in social functioning in a laboratory setting. Our battery of behavioral assays can be used to directly compare social outcome measures with both mouse models (i.e., high-throughput assays of sociability) and clinical populations (i.e., non-invasive eye tracking). With these developments, the nonhuman primate model is poised to provide a valuable test bed for evaluating innovative treatments targeting the core social deficits of ASD. We propose to first utilize this model to evaluate one of the most promising avenues of ASD treatment research - the oxytocin system. Although nasal oxytocin therapy is being promoted as a "safe and promising" therapy for ASD, we know very little about the efficacy or mechanism of oxytocin treatment in humans. Here we propose to utilize a well-characterized population of juvenile macaque monkeys to systematically evaluate the effects of intranasal oxytocin administration on primate sociability. We anticipate that the methods developed in the proposed research will result in a standard nonhuman primate testing platform that can be used to evaluate numerous future pharmacological interventions targeting the social deficits of ASD.

描述（由申请人提供）：虽然生命早期提供的强化行为干预改善了一些自闭症谱系障碍（ASD）儿童的社会功能，但当前的药理学治疗仅限于仅针对外围症状，例如侵略，焦虑和抑郁症。专门针对与行为干预同行提供的社会行为的新型药理学干预措施有望改善许多ASD患者的生活质量。亲社会药理治疗的开发将取决于将基本神经科学研究成功地转化为安全有效的药物，并且需要使用复杂的动物模型。尽管当前的ASD药物发现工作主要依赖于小鼠模型来评估复合功效，但针对ASD复杂的社会和交流缺陷的药理学干预措施最终可能需要使用与人类更紧密相关的动物模型。恒河猴由于在人类生理，神经解剖学和行为方面的相似之处而被认为是选择的生物医学模型物种。尽管目前尚无验证的ASD非人类灵长类动物模型，但我们认为，恒河猴社交性的自然变化提供了一种新型模型，以评估亲社会药理治疗的功效。我们已经建立了行为表型方案，可以在其出生场笼中识别低社会和高社会少年猴子，并可靠地量化实验室环境中社会功能的变化。我们的一系列行为分析可用于将社会结局指标与小鼠模型（即，具有社交性的高通量测定法）和临床人群（即非侵入性眼动追踪）进行比较。通过这些发展，非人类灵长类动物模型有望提供有价值的测试床，用于评估针对ASD核心社会缺陷的创新治疗方法。我们建议首先利用该模型评估ASD治疗研究最有希望的途径之一 - 催产素系统。尽管鼻催产素疗法被促进了ASD的“安全且有希望的”疗法，但我们对催产素治疗在人类中的疗效或机制知之甚少。在这里，我们建议利用特征良好的青少年猕猴人群系统地评估鼻内催产素对灵长类动物社交性的影响。我们预计拟议的研究中开发的方法将导致标准的非人类灵长类动物测试平台，该平台可用于评估针对ASD社会缺陷的许多未来药理干预措施。