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。虽然大脑感觉回路的缺陷被认为是ASD异常体感的主要原因，但最近发现了外周回路的贡献。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，而磷酸酶和紧张素同源物（Pten），一个已知的ASD易感基因，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，Pten突变体的初级感觉神经元的生存、细胞命运决定、分化和目标神经支配被破坏。现在，我将验证这一假设，即初级感觉神经元中Pten信号的改变会损害周围神经系统回路的发育，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：外周感觉神经元的存活改变、DRG亚群的异常多样化、神经元形态和神经支配模式的改变。在Specific Aim 1中，我将探讨这些细胞机制，并确定在体感觉发育过程中驱动致病变化的分子途径。在Specific Aim 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，并且我将确定由于Pten信号的破坏而改变的体感觉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背后的机制提供了基本的见解。我的长期目标是建立一个独立的研究路线，研究异常电路形成对ASD行为表型的贡献。因此，这个K01奖将为我提供1。通过研究计划培养自己的技术能力；2 .通过冷泉港和我所在机构的课程，在定量分析和成像技术方面获得了坚实的基础；在一个专门为博士后受训者提供专业发展的培训项目的协作环境中，与作为我的共同导师的资深科学家互动并收集专业建议。因此，这个奖项将帮助我获得方法论、智力和专业技能，以便在未来作为一名独立研究者进行出色的、定量严谨的研究。

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.