MOLECULAR REGULATION OF NOCICEPTIVE NEURON DEVELOPMENT

伤害性神经元发育的分子调控

• 批准号: 7381389
• 负责人: RICHARD F MURRAY
• 金额: $ 11.21万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381389
• 关键词: MOLECULAR; REGULATION; NOCICEPTIVE; NEURON; DEVELOPMENT

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.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，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。这些神经元源自迁移的神经嵴细胞，并且在神经原蛋白 1 (ngn1) 缺陷的小鼠中不存在，但人们对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丧失为表征调节伤害感受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，因此识别伤害性神经元祖细胞中调节 ngn1 表达的因子将有助于更好地了解该谱系的早期调节。此外，ngn1 下游效应器的识别将有助于更好地理解伤害性神经元分化。可能调节伤害性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，细胞培养实验表明 BMP 促进已知由伤害性神经元表达的神经肽的表达。为了鉴定参与伤害性神经元发育调节的因素，并检验内源表达的 BMP 调节伤害性神经元分化的假设，将追求以下具体目标：1）将鉴定 ngn1 启动子中的 DRG 特异性调节元件，作为鉴定上游调节因子的一种方法； 2) 通过微阵列分析比较野生型和ngn1无效DRG中的基因表达，鉴定ngn1基因的下游效应子； 3) BMP 在伤害性神经元发育中的作用将通过在体内伤害性神经元发育过程中上调和下调 BMP 信号来测试。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，并为疾病或损伤后的再生提供见解，并有可能缓解慢性疼痛。