Toll-like receptor signaling in sensory neuron differentiation and function.

感觉神经元分化和功能中的 Toll 样受体信号传导。

基本信息

批准号：
9066757
负责人：
Niels Ringstad
金额：
$ 31.21万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-05 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9066757
关键词：
Affect Afferent Neurons Animals Apnea Behavioral Mechanisms Biophysical Process Brain Brain Stem Breathing C. elegans genome Caenorhabditis elegans Carbon Dioxide Cell Respiration Cessation of life Cues Data Defect Detection Development Elements Embryo Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Screening Health Homologous Gene I-kappa B Proteins Inflammation Link Mammals Mediating Metabolic Microbe Mitogen-Activated Protein Kinases Molecular Motor Mutation Natural Immunity Nematoda Nervous system structure Neuronal Differentiation Neurons Pattern Physiological Physiology Play Proteins Receptor Signaling Respiratory Failure Role Signal Pathway Signal Transduction Study models Sudden infant death syndrome Toll-like receptors Vertebrates adapter protein avoidance behavior behavior test behavioral response carbon dioxide receptor gene function hindbrain meetings microbial mitogen-activated protein kinase p38 mutant nervous system disorder novel pathogen programs protein function receptor research study respiratory transcription factor

项目摘要

DESCRIPTION (provided by applicant): Chemosensory neurons specialized for the detection of carbon dioxide (CO2), a major product of aerobic metabolism, are present in the nervous systems of diverse animals. In vertebrates these neurons regulate breathing rhythms, and defects in CO2-sensing brain circuits are thought to underlie neurological disorders such as apneas and Sudden Infant Death Syndrome. Despite the critical roles that CO2-sensing neurons play in physiology, the molecular mechanisms required for their development and function remain poorly understood. Through genetic and physiological studies of CO2-sensing neurons of the nematode C. elegans we have established a powerful model for the study of such mechanisms. We have discovered that CO2-sensing neurons of C. elegans mediate a pathogen-avoidance behavior and require a Toll-like receptor (TLR) and its associated signaling pathway for their function. TLRs are evolutionarily conserved receptors that canonically function in embryonic patterning and innate immunity, and also function in the vertebrate nervous system to mediate inflammation. Our data indicate a previously unknown function for TLRs in the differentiation and function of sensory neurons and suggest a new role for TLRs in the vertebrate nervous system. Here we propose experiments to determine the molecular mechanisms by which TLR signaling promotes the differentiation and function of CO2-sensing neurons. These mechanisms will involve molecules required for TLR signaling, which is well known to play important roles in inflammation in the vertebrate brain and which our data suggest might also function in neuronal differentiation, as well as new components of the chemotransduction apparatus used for CO2-sensing.

描述（由申请人提供）：专门用于检测二氧化碳（CO2）的化学感应神经元（有氧代谢的主要产物）存在于多种动物的神经系统中。在脊椎动物中，这些神经元调节呼吸节奏，二氧化碳感应脑回路的缺陷被认为是神经系统疾病的基础，例如呼吸暂停和猝死综合征。尽管二氧化碳敏感性神经元在生理学中起着关键作用，但其发育和功能所需的分子机制仍然知之甚少。通过线虫秀丽隐杆线虫的二氧化碳神经元的遗传和生理研究，我们建立了一种强大的模型，用于研究此类机制。我们已经发现，秀丽隐杆线虫的二氧化碳神经元介导了病原体的避免行为，并需要收费样受体（TLR）及其功能的相关信号通路。 TLR是进化保守的受体，可以在胚胎模式和先天免疫中发挥作用，并且在脊椎动物神经系统中起作用以介导炎症。我们的数据表明，TLR在感觉神经元的分化和功能中的先前未知功能，并提出了TLR在脊椎动物神经系统中的新作用。在这里，我们提出了实验，以确定TLR信号促进二氧化碳感应神经元的分化和功能的分子机制。这些机制将涉及TLR信号所需的分子，众所周知，这在脊椎动物大脑的炎症中起着重要作用，我们的数据表明，这些机制也可能在神经元分化以及用于二氧化碳敏感性的趋化功能的新成分中起作用。