MOLECULAR REGULATION OF NOCICEPTIVE NEURON DEVELOPMENT

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。在神经系统中，疼痛是由位于脊髓两侧的背根节(DRG)中的伤害性神经元感受的。这些神经元来自迁移的神经脊细胞，在缺乏神经生成素1(Ngn1)的小鼠中缺失，但对调节这些神经元发育的分子机制知之甚少。Ngn1缺失动物的伤害性感受器的丢失为研究调控伤害性神经元发育的因素提供了一个重要的切入点。由于Ngn1是形成伤害性神经元祖细胞所必需的，识别调控伤害性神经前体细胞Ngn1表达的因素将有助于更好地理解这一谱系的早期调控。此外，识别Ngn1下游的效应器将有助于更好地理解伤害性神经元的分化。骨形态发生蛋白(BMPs)是可能调节伤害性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DRG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。为了确定参与调控伤害性感受神经元发育的因素，并检验内源性表达的BMPs调控伤害性感受神经元分化的假说，我们将致力于以下具体目标：1)鉴定Ngn1启动子中DRG特异的调控元件，作为识别上游调控因子的途径；2)通过比较野生型和Ngn1缺失DRGs中的基因表达，确定Ngn1基因的下游效应因子；以及3)通过上调和下调BMP信号在体内发育伤害性感受神经元中的作用，来检验BMP在伤害性感受神经元发育中的作用。这项研究将有助于我们了解发育中的神经系统中神经元的生长和分化，并应为疾病或损伤后的再生提供见解，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.