Role of endothelins in SCG axon guidance

内皮素在 SCG 轴突引导中的作用

基本信息

批准号：
7663092
负责人：
Takako Makita
金额：
$ 9万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2009-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7663092
关键词：
Address Axon Blood Vessels Cell Lineage Cells Complex Congenital Abnormality Cues Defect Development EDN1 gene Embryo Endothelin 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 Organ Organ Transplantation Phenotype Process Production 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 neuron development paralogous gene programs public health relevance receptor expression receptor function reinnervation relating to nervous system research study response

项目摘要

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关键过程是新生神经元投射的轴突选择接触和支配目标器官的方式。该提案介绍了内皮素信号传导作为一种关键机制的作用，该机制控制了宫颈上神经节（SCG）的交感神经投影。该提案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蛋白为来自SCG的交感神经轴突提供了指导线索，从而沿外部颈动脉采用特定的血管轨迹。 SCG神经元的一个子集表达了A型内皮素受体（ETA），这对于SCG轴突在不同的轨迹之间进行选择至关重要，以支配其适当的靶组织。在此应用中，我提出了实验，以解决和扩展一个模型，在该模型中，内皮素信号传导从外部颈动脉的平滑肌发出，是SCG轴突的必需指导提示。特定目标1：定义SCG轴突指导中内皮素信号成分的遗传要求。该目的旨在解决平滑肌的内皮素配体的机理，特别是外部颈动脉的机理。特定目的2：定义SCG轴突指导中内皮素信号成分的组织特异性功能。该目的解决了SCG神经元本质上要求ETA反应内皮素以沿外部颈动脉进行预测的程度。特定AIM3：定义HOXA3突变小鼠中SCG出生缺陷的分子基础。在此目标中，我将评估HOXA3突变小鼠中内皮素信号成分的表达如何受到干扰，而Hoxa3突变小鼠的表达如何具有可比的SCG生长缺乏症。公共卫生相关性：这项研究涉及神经血管一致性的分子基础和在发育过程中建立适当的神经回路，这两者都与神经神经神经神经神经神经的先天性缺陷的治疗以及神经疾病后神经回路的再生有关。学到的原则还将适用于器官移植研究，以使截肢轴突重新接触到移植器官。