Role of endothelins in SCG axon guidance

内皮素在 SCG 轴突引导中的作用

• 批准号: 7510755
• 负责人: Takako Makita
• 金额: $ 9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7510755
• 关键词: Address; Axon; Blood Vessels; Cell Lineage; Cells; Complex; Congenital Abnormality; Cues; Defect; Development; EDN1 gene; Embryo; Endothelin; Endothelin A Receptor; Endothelin Receptor; Evolution; External carotid artery structure; Gene Expression; Genetic; In Vitro; Indium; Injury; Lead; Learning; Ligands; Modeling; Molecular; Mutant Strains Mice; Natural regeneration; Nerve; Nervous system structure; Neurologic; Neurons; Numbers; Organ; Organ Transplantation; Phenotype; Process; Production; Public Health; Recording of previous events; Relative (related person); Research; Research Personnel; Role; Signal Transduction; Site; Smooth Muscle; Structure of superior cervical ganglion; Time; Tissues; Vascular Smooth Muscle; axon guidance; base; combinatorial; developmental neurobiology; endothelin-converting enzyme; gene function; mutant; nerve supply; neural circuit; paralogous gene; programs; receptor expression; receptor function; reinnervation; relating to nervous system; research study; response

DESCRIPTION (provided by applicant): A key process in developmental neurobiology is the manner by which axons projecting from newly born neurons choose paths to reach and innervate target organs. This proposal addresses the role of endothelin signaling as a critical mechanism that controls the projection of sympathetic axons from the superior cervical ganglia (SCG). New observations described in this proposal lead to a model in which vascular smooth muscle-derived endothelins provide guidance cues for sympathetic axons from the SCG to take a specific vascular trajectory, along the external carotid artery. A subset of SCG neurons express the type A endothelin receptor (ETA), which is essential for SCG axons to choose between distinct trajectories and to innervate their appropriate target tissues. In this application, I propose experiments to address and extend a model in which endothelin signaling, emanating from smooth muscle of the external carotid arteries, is a required guidance cue for SCG axons. Specific Aim1: To define the genetic requirements for endothelin signaling components in SCG axon guidance. This aim addresses the mechanism of endothelin ligand production by smooth muscle specifically of the external carotid arteries. Specific Aim 2: To define the tissue-specific functions of endothelin signaling components in SCG axon guidance. This aim addresses the extent to which ETA is intrinsically required by SCG neurons to respond endothelins in order to project along the external carotid arteries. Specific Aim3: To define the molecular basis of defective SCG outgrowth in Hoxa3 mutant mice. In this aim, I will evaluate how expression of endothelin signaling components is perturbed in Hoxa3 mutant mice, which have a comparable SCG outgrowth deficiency as seen in ETA-deficient embryos. Public health relevance: This research addresses the molecular basis of nerve-blood vessel congruency and the establishment of proper neural circuitry during development, both of which are relevant to the treatment for congenital defects in neural innervations, and for regeneration of neural circuitry following neurological diesease or injury. The principles learned will also apply to organ transplantation studies to achieve reinnervation of amputated axons to transplanted organs.

描述(由申请人提供)： 发育神经生物学中的一个关键过程是新生神经元投射的轴突选择到达和支配靶器官的路径的方式。这项建议阐述了内皮素信号作为控制交感神经节(SCG)交感轴突投射的关键机制所起的作用。这项建议中描述的新观察结果导致了一个模型，在该模型中，血管平滑肌衍生的内皮素为来自SCG的交感轴突提供指导信号，使其沿着颈外动脉沿特定的血管轨迹运动。一部分SCG神经元表达A型内皮素受体(ETA)，这对SCG轴突在不同的轨迹之间进行选择和对其适当的靶组织进行神经支配是必不可少的。在这个应用中，我建议进行实验来解决和扩展一个模型，在该模型中，从颈外动脉的平滑肌肉发出的内皮素信号是SCG轴突所必需的指导信号。 具体目的1：明确SCG轴突指导中对内皮素信号成分的遗传要求。本研究的目的是探讨颈外动脉平滑肌产生内皮素配体的机制。 具体目的2：明确内皮素信号成分在SCG轴突引导中的组织特异性功能。本研究的目的是解决SCG神经元为了沿着颈外动脉投射而对内皮素作出反应时所需的ETA的内在程度。 目的：明确Hoxa3突变小鼠SCG突起缺陷的分子基础。在这个目标中，我将评估Hoxa3突变小鼠的内皮素信号成分的表达是如何受到干扰的，这些突变小鼠与ETA缺陷的胚胎具有类似的SCG生长缺陷。 公共卫生相关性：这项研究解决了神经-血管一致性的分子基础和发育过程中适当的神经回路的建立，这两者都与治疗神经神经先天缺陷和神经疾病或损伤后神经回路的再生有关。学习的原则也将适用于器官移植研究，以实现被截断的轴突对移植器官的再神经支配。