MOLECULAR REGULATION OF NOCICEPTIVE NEURON DEVELOPMENT

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。在神经系统中，疼痛是由位于脊髓侧面的背根神经节（DRG）中的伤害性神经元感知的。这些神经元来源于迁移的神经嵴细胞，在神经原蛋白1 （ngn1）缺乏的小鼠中缺失，但关于调节这些神经元发育的分子机制知之甚少。ngn1缺失动物中伤害感受器的缺失为研究调节伤害神经元发育的因素提供了一个重要的切入点。由于ngn1是其形成所必需的，因此确定在痛觉神经元祖细胞中调节ngn1表达的因子将有助于更好地理解这一谱系的早期调控。此外，鉴定ngn1下游的效应物将有助于更好地理解伤害神经元的分化。骨形态发生蛋白（BMPs）可能是调节伤害神经元发育的潜在候选者。BMP配体以及I型和II型BMP受体在发育中的DRGs中表达，细胞培养实验表明BMP促进一种已知由伤害性神经元表达的神经肽的表达。为了确定参与伤害神经元发育调节的因素，并验证内源性表达的bmp调节伤害神经元分化的假设，将追求以下具体目标：1)在ngn1启动子中确定DRG特异性调节元件，作为识别上游调节因子的一种方式；2)通过基因芯片分析，比较野生型和无ngn1基因DRGs的基因表达，鉴定ngn1基因的下游效应物；3)通过在体内研究损伤神经元发育过程中BMP信号的上调和下调，来验证BMP在损伤神经元发育中的作用。这项研究将有助于我们理解神经系统发育中的神经元生长和分化，并为疾病或损伤后的再生提供见解，并有可能减轻慢性疼痛。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the nervous system, pain is sensed by nociceptive neurons that reside in the dorsal root ganglia (DRG) that flank the spinal cord. These neurons derive from migrating neural crest cells and are absent in mice deficient in neurogenin1 (ngn1), but little else is known about the molecular mechanisms that regulate the development of these neurons. The loss of nociceptors in ngn1 null animals provides an important entry point into the characterization of factors that regulate nociceptive neuron development. Since ngn1 is required for their formation, identification of factors that regulate ngn1 expression in nociceptive neuron progenitors will lead to a better understanding of the early regulation of this lineage. Also, identification of effectors downstream of ngn1 will lead to a better understanding of nociceptive neuron differentiation. Potential candidates that may regulate nociceptive neuron development are the bone morphogenetic proteins (BMPs). BMP ligands, as well as type I and type II BMP receptors, are expressed in developing DRGs, and cell culture experiments have shown that BMPs promote the expression of a neuropeptide known to be expressed by nociceptive neurons. To identify factors involved in the regulation of nociceptive neuron development and to test the hypothesis that endogenously expressed BMPs regulate the differentiation of nociceptive neurons, the following specific aims will be pursued: 1) DRG specific regulatory elements in the ngn1 promoter will be identified as a way to identify upstream regulatory factors; 2) downstream effectors of the ngn1 gene will be identified by comparing gene expression in wild type and ngn1 null DRGs by microarray analysis; and 3) the role of BMPs in nociceptive neuron development will be tested by up- and downregulating BMP signaling in developing nociceptive neurons in vivo. This study will contribute to our understanding of neuronal growth and differentiation in the developing nervous system and should provide insights into regeneration following disease or injury, and potentially for alleviating chronic pain.