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

描述(申请人提供)：专门用于检测二氧化碳(二氧化碳)的化学感觉神经元存在于各种动物的神经系统中，二氧化碳是有氧代谢的主要产物。在脊椎动物中，这些神经元调节呼吸节奏，而二氧化碳感应脑回路的缺陷被认为是呼吸暂停和婴儿猝死综合症等神经疾病的基础。尽管二氧化碳敏感神经元在生理学中扮演着重要的角色，但其发育和功能所需的分子机制仍然知之甚少。通过对线虫对二氧化碳敏感神经元的遗传学和生理学研究，我们建立了一个强有力的模型来研究这种机制。我们发现线虫的二氧化碳敏感神经元介导了一种病原体回避行为，需要Toll样受体(TLR)及其相关的信号通路才能发挥作用。TLRs是进化上保守的受体，在胚胎模式和先天免疫中发挥规范功能，也在脊椎动物神经系统中发挥介导炎症的功能。我们的数据表明TLRs在感觉神经元的分化和功能中具有以前未知的功能，并提示TLRs在脊椎动物神经系统中的新作用。在这里，我们建议通过实验来确定TLR信号促进二氧化碳敏感神经元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，TLR信号在脊椎动物大脑的炎症中发挥重要作用，我们的数据表明，TLR信号也可能在神经元分化中发挥作用，以及用于二氧化碳传感的化学转导装置的新组件。

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.