The role of Pten on primary sensory neuron development

感觉处理改变是自闭症谱系障碍（ASD）的一个共同特征。虽然有缺陷的感觉电路在大脑中被认为是强调异常的躯体感觉在ASD，周边电路的贡献最近已被确定。神经营养因子/trk信号转导控制着体感神经发育的多个方面，而已知的ASD易感基因磷酸酶和张力蛋白同源物（Pten）作为该途径的关键负调节因子发挥作用。然而，Pten的丢失如何影响初级感觉神经元的存活、群体多样性以及回路的形成和功能仍有待确定。我的初步数据表明，生存，细胞命运的决定，分化，和目标神经支配中断在Pten突变体的初级感觉神经元。现在，我将检验一个假设，即初级感觉神经元中Pten信号的改变会影响外周神经系统回路的发育，最终导致感觉处理的改变。有几个不同的机制，Pten缺失可能会影响外周感觉回路的发展：外周感觉神经元的存活改变，异常DRG亚群多样化，改变神经元形态和神经支配模式。在具体目标1中，我将询问这些细胞机制，并确定在体感发育过程中驱动致病变化的分子途径。在具体目标2中，我将定义Pten的缺失如何改变初级感觉神经元的神经支配模式，我将确定由于Pten信号传导中断而改变的体感神经元发育和功能是否有助于感觉表型。总之，该项目将建立周围神经系统发育中特定细胞缺陷与电路组织和功能改变之间的关系;为ASD关键临床特征的机制提供基本见解。我的长期目标是发展一个独立的研究路线，研究异常回路形成对ASD行为表型的贡献。因此，这个K 01奖将为我服务1。通过研究计划发展我的技术技能，2.通过在冷泉港和我的家乡机构的课程，获得了定量分析和成像技术的坚实基础;在一个合作的环境中，与担任我的共同导师的资深科学家进行互动并收集专业建议，该环境具有专门为博士后学员提供专业发展的培训计划。因此，这个奖项将帮助我获得方法，智力和专业技能，在未来作为一个独立的研究者进行杰出的，定量的严格研究。

Altered sensory processing is a common feature of autism spectrum disorders (ASD). Although defective sensory circuitry in the brain is believed to underline abnormal somatosensation in ASD, a contribution of peripheral circuitry has been recently identified. Neurotrophin/trk signaling controls multiple aspects of somatosensory neurodevelopment, and phosphatase and tensin homolog (Pten), a known ASD susceptibility gene, functions as a key negative regulator of this pathway. However, it remains to be determined how loss of Pten affects primary sensory neuron survival, population diversity and circuit formation and function. My preliminary data suggest that survival, cell-fate determination, differentiation, and target innervation are disrupted in primary sensory neurons in Pten mutants. I will now test the hypothesis that altered Pten signaling in primary sensory neurons compromises peripheral nervous system circuit development, ultimately leading to altered sensory processing. There are several distinct mechanisms by which Pten deletion may affect the development of peripheral sensory circuits: altered survival of peripheral sensory neurons, abnormal DRG subpopulation diversification, and altered neuronal morphology and innervation patterns. In Specific Aim 1, I will interrogate these cellular mechanisms and identify the molecular pathways that drive pathogenic changes during somatosensory development. In Specific Aim 2, I will define how loss of Pten alters innervation patterns of primary sensory neurons, and I will determine whether altered somatosensory neuron development and function, due to disrupted Pten signaling, contributes to sensory phenotypes. Altogether, this project will establish the relationship between specific cellular defects in the developing peripheral nervous system and altered circuit organization and function; offering fundamental insight into the mechanisms underlying a key clinical feature of ASD. My long-term goal to develop an independent line of research studying the contribution of abnormal circuit formation to the behavioral phenotypes in ASD. Thus, this K01 award will serve me to 1. develop my technical skills through the research plan, 2. acquire a strong foundation in quantitative analysis as well as in imaging techniques, through courses at the Cold Spring Harbor and in my home institution, and 3. interact and gather professional advice from senior scientists who serve as my co-mentors, in a collaborative environment that has a training program designed specifically to provide professional development to post-doctoral trainees. Thus, this award will serve me to acquire the methodological, intellectual and professional skills to conduct outstanding, quantitatively rigorous research in the future as an independent investigator.