Understanding Somatosensory Deficits in Autism Spectrum Disorders

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。我的研究兴趣包括利用基础生物医学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。我使用了一系列小鼠ASD遗传模型，结合行为测试、解剖学和突触分析来定义ASD异常触觉敏感性的病因，以及外周体感神经元功能障碍对ASD样特征表达的贡献(Orefice等人，Cell，2016)。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军人物金蒂博士指导。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人目前在一流研究型大学担任教职。共同发起人也在HMS，他们都是久负盛名的科学家，在神经科学方面有出色的发表和培训记录，并在本培训计划中建议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，包括在冷泉港举行的为期3周的强化课程--“突触和神经回路生理学中的离子通道”。我还将参加有关自闭症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，我指导了两名本科生，并为几名研究生提供指导经验。研究计划：我最近的工作揭示了ASD患者异常触觉知觉的一个功能障碍，这一点令人惊讶地超出了大脑。我发现，脊髓内外周体感神经元突触的发育障碍导致异常的触觉处理，是导致成年MeCP2和GABRB3小鼠模型ASD焦虑样行为和社会互动缺陷的主要原因。这项应用将利用行为学、组织学和电生理学将这些初步发现扩展到新的基础研究方向，并朝着新的治疗策略的发展方向发展。在K99阶段，我将确定外周躯体感觉神经元缺陷是否是其他ASD模型(Shank3，Fmr1)功能障碍的常见原因(目标1)。其次，我将确定外周作用的基因疗法和小分子疗法来治疗ASD小鼠模型的触觉过敏，目标是减轻躯体感觉、焦虑样和社会互动缺陷(目标2)。R00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、解剖示踪和活体成像来了解外周躯体感觉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)。

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).