The role of Pten on primary sensory neuron development

感觉加工改变是自闭症谱系障碍(ASD)的一个共同特征。虽然大脑感觉回路的缺陷被认为是ASD躯体感觉异常的原因，但最近发现了外周回路的作用。神经营养因子/trk信号控制着躯体感觉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基因(Pten)是这一途径的关键负调控因子。然而，Pten的缺失如何影响初级感觉神经元的存活、种群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，在Pten突变体中，初级感觉神经元的存活、细胞命运决定、分化和靶神经支配受到破坏。我现在要验证的假设是，初级感觉神经元中Pten信号的改变会损害周围神经系统的回路发育，最终导致感觉处理的改变。Pten缺失可能通过几种不同的机制影响外周感觉回路的发育：外周感觉神经元存活改变，DRG亚群异常多样化，以及神经元形态和神经支配模式改变。在具体目标1中，我将询问这些细胞机制，并确定在躯体感觉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的丢失如何改变初级感觉神经元的神经模式，并将确定由于Pten信号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，该项目将建立发育中的周围神经系统中特定的细胞缺陷与改变的电路组织和功能之间的关系；为ASD的一个关键临床特征的潜在机制提供基本的见解。我的长期目标是发展一项独立的研究，研究异常回路形成对ASD行为表型的贡献。因此，这个K01奖项将帮助我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，在定量分析和成像技术方面获得坚实的基础，以及3.在一个有专门为博士后学员提供专业发展的培训计划的协作环境中，互动并收集作为我的共同导师的资深科学家的专业建议。因此，这一奖项将有助于我获得方法论、智力和专业技能，以作为一名独立调查员在未来进行杰出的、数量上严格的研究。

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.