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.

改变的感觉处理是自闭症谱系障碍（ASD）的常见特征。尽管据信大脑中有缺陷的感觉电路强调了ASD中异常的体质，但最近已经确定了周围电路的贡献。神经营养蛋白/TRK信号控制体感神经发育的多个方面，以及已知的ASD敏感性基因的磷酸酶和Tensin同源物（PTEN）作为该途径的关键负调节剂。但是，尚待确定PTEN的损失如何影响原发性感觉神经元的存活，种群多样性以及电路形成和功能。我的初步数据表明，在PTEN突变体的原发性感觉神经元中，生存，阳离子测定，分化和靶神经受到破坏。现在，我将检验以下假设，即主感觉神经元中的PTEN信号传导损害了周围神经系统电路的发育，最终导致感觉处理改变。 PTEN缺失可能会影响周围感觉电路的发展：周围感觉神经元的存活改变，DRG亚群多样性以及神经元形态和神经神经化模式的改变。在特定的目标1中，我将询问这些细胞机制，并确定在体感发展过程中驱动致病性变化的分子途径。在特定的目标2中，我将定义PTEN丧失如何改变原发性神经元的神经神经模式，并且我将确定由于PTEN信号破坏而改变的体感神经元的发育和功能是否有助于感觉表型。总的来说，该项目将建立发育中的周围神经系统中特定细胞缺陷与电路组织和功能改变的关系。提供对ASD关键临床特征的基础机制的基本见解。我的长期目标是开发独立的研究线，研究了异常电路形成对ASD行为表型的贡献。因此，这项K01奖将使我为1。通过研究计划，2。通过量化分析以及成像技术，通过在冷春港和我的家庭机构中的课程以及3。互动并收集高级科学家的专业建议，在我的合作环境中提供专业培训专业发展的高级科学家的专业建议。因此，该奖项将使我获得方法论，智力和专业技能，以作为独立研究人员在未来进行杰出的，定量严格的研究。