MOLECULAR REGULATION OF NOCICEPTIVE NEURON DEVELOPMENT

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在神经系统中，疼痛由位于脊髓侧面的背根神经节（DRG）中的伤害感受神经元感知。这些神经元来源于迁移的神经嵴细胞，在缺乏神经生成素1（ngn 1）的小鼠中是不存在的，但是关于调节这些神经元发育的分子机制，我们知之甚少。ngn 1基因缺失动物伤害感受器的缺失为描述伤害感受神经元发育的调控因子提供了一个重要的切入点。由于ngn 1是其形成所必需的，因此鉴定伤害性神经元祖细胞中ngn 1表达的调控因子将有助于更好地理解这一谱系的早期调控。此外，ngn 1下游效应子的鉴定将导致对伤害感受神经元分化的更好理解。可能调节伤害感受神经元发育的潜在候选者是骨形态发生蛋白（BMP）。BMP配体以及I型和II型BMP受体在发育中的DRG中表达，并且细胞培养实验已经表明BMP促进已知由伤害感受神经元表达的神经肽的表达。为了鉴定参与伤害感受神经元发育调节的因子并检验内源性表达的BMP调节伤害感受神经元分化的假设，将追求以下具体目标：1）将鉴定ngn 1启动子中DRG特异性调节元件作为鉴定上游调节因子的一种方式; 2）ngn 1基因的下游效应物将通过微阵列分析比较野生型和ngn 1无效DRG中的基因表达来鉴定;和3）BMP在伤害感受神经元发育中的作用将通过在体内发育的伤害感受神经元中上调和下调BMP信号传导来测试。这项研究将有助于我们了解神经系统发育中的神经元生长和分化，并应提供疾病或损伤后再生的见解，并有可能缓解慢性疼痛。

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.