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

描述（由申请人提供）：专门用于检测二氧化碳（CO2）（有氧代谢的主要产物）的化学感觉神经元存在于各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律，而二氧化碳感知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系统疾病的基础。尽管CO2敏感神经元在生理学中发挥着重要作用，但其发育和功能所需的分子机制仍然知之甚少。通过对C.我们已经建立了一个强大的模型，研究这种机制。我们发现C.线虫介导病原体回避行为，并且需要Toll样受体（TLR）及其相关的信号通路来实现其功能。TLR是进化上保守的受体，其在胚胎图案形成和先天免疫中起典型作用，并且还在脊椎动物神经系统中起介导炎症的作用。我们的数据表明，以前未知的功能TLRs的分化和感觉神经元的功能，并提出了一个新的作用，TLRs在脊椎动物神经系统。在这里，我们提出的实验，以确定TLR信号促进CO2敏感神经元的分化和功能的分子机制。这些机制将涉及TLR信号传导所需的分子，众所周知，TLR信号传导在脊椎动物大脑的炎症中起重要作用，我们的数据表明TLR信号传导也可能在神经元分化中起作用，以及用于CO2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.