The role of Pten on primary sensory neuron development

Pten 对初级感觉神经元发育的作用

基本信息

批准号：
10155600
负责人：
Alejandra Fernandez
金额：
$ 9.79万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10155600
关键词：
Affect Afferent Neurons Apoptosis Apoptotic Award Axon Behavior Behavioral Assay Brain Cell Cycle Cell Death Cell Death Signaling Process Cell Differentiation process Cell Survival Cells Clinical Cre driver Data Defect Development Developmental Process Embryo FRAP1 gene Foundations Future Gene Dosage Goals Home Imaging Techniques In Vitro Institution Label Link MAPK8 gene Mediating Mentored Research Scientist Development Award Mentors Methodology Molecular Morphology Mus Mutation NGFR Protein Neuronal Differentiation Neurons Nociception Nociceptors PTEN gene Parvalbumins Pathogenicity Pathway interactions Pattern Peripheral Peripheral Nervous System Phase Phenotype Population Population Heterogeneity Postdoctoral Fellow Proprioceptor Regulation Research Research Personnel Role S Phase Senior Scientist Sensory Signal Pathway Signal Transduction Spinal Cord Susceptibility Gene Technical Expertise Testing Training Programs anxiety-like behavior autism spectrum disorder base behavioral phenotyping collaborative environment design dosage experimental study gene function in vivo insight mature animal mouse model mutant nerve injury nerve supply nervous system development neural circuit neurodevelopment neuron development neuronal survival neurotransmission neurotrophic factor postnatal research study skills social deficits somatosensory

项目摘要

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.

感觉处理改变是自闭症谱系障碍 (ASD) 的一个共同特征。尽管大脑中的感觉回路缺陷被认为是自闭症谱系障碍患者躯体感觉异常的重要原因，但最近已发现外周回路的贡献。神经营养素/trk 信号传导控制体感神经发育的多个方面，磷酸酶和张力蛋白同源物 (Pten)（一种已知的 ASD 易感基因）充当该通路的关键负调节因子。然而，Pten 的缺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，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受到破坏。我现在将检验以下假设：初级感觉神经元中 Pten 信号传导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 亚群多样化异常以及神经元形态和神经支配模式改变。在具体目标 1 中，我将探讨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，并且我将确定由于 Pten 信号传导破坏而导致的体感神经元发育和功能的改变是否会导致感觉表型。总而言之，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回路组织和功能之间的关系；提供对 ASD 关键临床特征背后机制的基本见解。我的长期目标是开发一条独立的研究路线，研究异常回路形成对自闭症谱系障碍行为表型的贡献。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. 通过冷泉港和我所在机构的课程，在定量分析和成像技术方面打下坚实的基础，以及3. 在一个协作环境中，与作为我的共同导师的资深科学家互动并收集专业建议，该环境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论、智力和专业技能，以便将来作为一名独立研究者进行出色的、定量严谨的研究。