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Understanding Somatosensory Deficits in Autism Spectrum Disorders

了解自闭症谱系障碍的体感缺陷

基本信息

批准号：
9906939
负责人：
Lauren Lynn Orefice
金额：
$ 27.72万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906939
关键词：
Adult Affect Afferent Neurons Agonist Amyloid beta-Protein Anatomy Anxiety Area Attention Award Basic Science Behavior Behavioral Biology Biomedical Research Blood - brain barrier anatomy Brain Calcium Cells Centers for Disease Control and Prevention (U.S.)Child Cognition Cognitive Data Development Diagnosis Educational workshop Electrophysiology (science)Environment Etiology Exhibits FDA approved FMR1 Faculty Functional disorder Gene Deletion Gene Mutation Genes Genetic Genetic Models Glean Goals HCN1 gene Histology Hypersensitivity Image Imaging Techniques Impairment Inherited Ion Channel Knockout Mice Laboratories Lead Link Mediating Mentors Mentorship Methyl-CpG-Binding Protein 2 Modeling Molecular Molecular Target Mus Mutant Strains Mice Mutation Nervous System Physiology Nervous system structure Neurobiology Neurodevelopmental Disorder Neurons Neurosciences Pathogenesis Patients Perception Peripheral Peripheral Nervous System Pharmacological Treatment Pharmacotherapy Phase Phenotype Physiology Population Positioning Attribute Postdoctoral Fellow Presynaptic Terminals Publications Records Research Scientist Sensory Skin Social Behavior Social Development Social Interaction Spinal Cord Spinal cord posterior horn Symptoms Synapses Syndrome System Tactile Techniques Testing Therapeutic Touch sensation Training Training Activity Universities Viral Work anatomical tracing anxiety-like behavior autism spectrum disorder barrel cortex behavior test brain abnormalities career development effective therapy experience experimental study gene therapy genetic approach graduate student improved in vivo imaging insight interest medical schools meetings mouse genetics mouse model neural circuit neuron development novel novel strategies novel therapeutics presynaptic receptor repetitive behavior response restoration sensory stimulus skills small molecule therapeutics social social communication somatosensory therapeutic development therapeutic target tool trait translational approach undergraduate student

项目摘要

Candidate: I am a postdoctoral fellow in Dr. David Ginty's laboratory at Harvard Medical School. My research interests include using basic biomedical research to study the mechanisms of dysfunction in Autism Spectrum Disorders (ASD) and developing translational strategies for novel potential therapeutic approaches. I have used a range of mouse ASD genetic models combined with behavioral testing, anatomy, and synaptic analyses to define both the etiology of aberrant tactile sensitivity in ASD and the contribution of peripheral somatosensory neuron dysfunction to the expression of ASD-like traits (Orefice et al., Cell, 2016). Environment: Research will be conducted at Harvard Medical School (HMS) under the mentorship of Dr. Ginty, a leader in the field of somatosensory neurobiology. Dr. Ginty has an excellent mentorship record, with 13 of his past 14 postdoctoral fellows now in faculty positions at leading research universities. The co- sponsors, also at HMS, are all well-established scientists with excellent publication and training records in neuroscience and expertise in the techniques proposed in this training plan. Career Development: Training activities will include the mastery of electrophysiological techniques by performing experiments and attending workshops/courses, including an intensive 3-week `Ion Channels in Synaptic and Neural Circuit Physiology' course at Cold Spring Harbor. I will also attend scientific meetings focused on ASD and somatosensory biology. Third, I will acquire skills for applying basic research to potential therapeutic applications. Finally, I will hone skills required for managing an independent laboratory. Currently, I mentor two undergraduates and provide guidance to several graduate students for mentorship experience. Research Plan: My recent work revealed a locus of dysfunction underlying aberrant tactile perception in ASD that was surprisingly outside the brain. I found that developmental dysfunction of peripheral somatosensory neurons at their synapses within the spinal cord results in abnormal tactile processing and is a major contributor to anxiety-like behavior and social interaction deficits in adult Mecp2 and Gabrb3 mouse models of ASD. This application will utilize behavior, histology and electrophysiology to extend these preliminary findings in new basic research directions and toward the development of novel therapeutic strategies. During the K99 phase, I will determine whether peripheral somatosensory neuron deficits are a common cause of dysfunction in other models of ASD (Shank3, Fmr1) (Aim 1). Second, I will identify peripherally acting gene therapies and small molecule therapeutics to treat tactile hypersensitivity in ASD mouse models, with the goal of alleviating somatosensory, anxiety-like and social interaction deficits (Aim 2). The focus of the R00 phase will be to continue therapeutic development as started in Aim 2 and to use electrophysiology, anatomical tracing and in vivo imaging to understand how peripheral somatosensory dysfunction affects brain development and ultimately leads to anxiety-like behavior and social interaction deficits in ASD mouse models (Aim 3).

候选人：我是哈佛医学院大卫金蒂博士实验室的博士后研究员。我的研究兴趣包括使用基础生物医学研究来研究自闭症谱系障碍（ASD）的功能障碍机制，并为新的潜在治疗方法开发翻译策略。我已经使用了一系列小鼠ASD遗传模型与行为测试、解剖学和突触分析相结合，以定义ASD中异常触觉敏感性的病因学和外周体感神经元功能障碍对ASD样性状表达的贡献（Orefice et al.，Cell，2016）。工作环境：研究将在哈佛医学院（HMS）进行，由体感神经生物学领域的领导者Ginty博士指导。金蒂博士有着出色的导师记录，他过去的14名博士后研究员中有13名现在在领先的研究型大学担任教职。共同发起人，也在HMS，都是在神经科学方面有着出色的出版和培训记录的知名科学家，并且在本培训计划中提出的技术方面具有专业知识。职业发展：培训活动将包括通过进行实验和参加讲习班/课程掌握电生理技术，包括在冷泉港举办为期3周的“突触和神经回路生理学中的离子通道”强化课程。我还将参加专注于ASD和体感生物学的科学会议。第三，我将获得将基础研究应用于潜在治疗应用的技能。最后，我将磨练管理独立实验室所需的技能。目前，我指导两名本科生，并为几名研究生提供指导。研究计划：我最近的工作揭示了ASD中异常触觉感知的功能障碍部位，令人惊讶的是在大脑之外。我发现脊髓内突触处的外周体感神经元的发育功能障碍导致异常的触觉处理，并且是成人Mecp 2和Gabrb 3 ASD小鼠模型中焦虑样行为和社会互动缺陷的主要贡献者。该应用程序将利用行为学，组织学和电生理学来扩展新的基础研究方向和新的治疗策略的发展这些初步发现。在K99阶段，我将确定外周体感神经元缺陷是否是其他ASD模型（Shank 3，Fmr 1）功能障碍的常见原因（目的1）。其次，我将确定外周作用基因疗法和小分子疗法来治疗ASD小鼠模型中的触觉超敏反应，目的是减轻躯体感觉，焦虑样和社会互动缺陷（目标2）。R 00阶段的重点将是继续目标2中开始的治疗开发，并使用电生理学，解剖追踪和体内成像来了解外周体感功能障碍如何影响大脑发育，并最终导致ASD小鼠模型中的焦虑样行为和社会互动缺陷（目标3）。