Determining the Molecular Mechanisms of Vascular Sympathetic Innervation

确定血管交感神经支配的分子机制

基本信息

批准号：
7600367
负责人：
Jennifer B Long
金额：
$ 0.72万
依托单位：
YALE 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：
2008-03-05 至 2009-09-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7600367
关键词：
3-Dimensional Actins Adult Age Animals Arteries Automobile Driving Axon Bacteria Biological Assay Blocking Antibodies Blood Vessels Blood capillaries Blood flow CD31 Antigens Candidate Disease Gene Cardiac Carotid Arteries Cavia Cells Coculture Techniques Collagen Coronary Vessels Cues Culture Media Denervation Development Disease Distal Ear Embryo Endothelial Cells Environment Etiology Exercise Gel Gene Expression Genes Hypertension Immunofluorescence Immunologic In Vitro Individual Length Life Mediating Mesentery Messenger RNA Microspheres Modeling Molecular Molecular Profiling Mus Names Nerve Nerve Plexus Neural Crest Cell Neurites Neurons Organ Oryctolagus cuniculus Parkinson Disease Pathway interactions Patients Pattern Peripheral Play RNA Interference Rattus Role Sampling Sequence Homology Series Smooth Muscle Stress Structure of superior cervical ganglion Sympathetic Ganglia Sympathetic Nervous System Synapses Synaptophysin Techniques Temperature Time Tissue Sample Tissues Transcript Transplantation Travel Tyrosine 3-Monooxygenase Variant Varicosity Vascular resistance Veins Western Blotting axon guidance base blood pressure regulation capillary cell type cremaster muscle density design ethylenevinylacetate copolymer feeding femoral artery in vivo knock-down mRNA Expression migration nerve supply neuroblast neurogenesis neuron development peripheral blood postnatal protein expression receptor repaired research study response spatiotemporal synaptogenesis venule

项目摘要

DESCRIPTION (provided by applicant): The sympathetic nervous system is integral to blood pressure regulation through changes in peripheral vascular resistance. Sympathetic nerves typically innervate major feed arteries and extend through the precapillary arteriolar network, but not into capillaries, venules or collecting veins. During development, axon extension closely follows arteries as neurons approach and innervate target organs. This close proximity to blood vessels suggests that vessel derived molecules may play a role in axon outgrowth and target innervation. Due to the selective sympathetic innervation of pre-capillary vessels, our hypothesis is that molecular cues that could promote chemoattraction between arteries and neurons or chemorepulsion between veins and neurons exist and may be expressed by vascular cells. Our specific aims are designed to allow us to identify candidate molecules that may drive selective vascular sympathetic innervation and evaluate their functions in vitro. We will (1) characterize sympathetic innervation patterns and synapse formation by immunofluorescence in several blood vessels in late embryonic and postnatal animals, (2) conduct a subtractive hybridization of innervated and non-innervated vessels to generate a list of differentially expressed candidate molecules and validate their expression through western blot and immunofluorescence and (3) evaluate the functional impacts of any identified candidate molecules using a three-dimensional (3-D) co-culture model using superior cervical ganglion explants with innervated and non-innervated vessel segments to assess directed neurite outgrowth in response to the application of identified candidate molecules to the culture medium. Relevance: Alterations in vascular sympathetic has been implicated in diseases such as hypertension (hyperinnervation) and the pathological sequalae following cardiac transplant (denervation). For example, loss of sympathetic neurons after transplant compromises the ability to regulate peripheral blood flow and to adequately tolerate exercise, temperature fluctuations and other physical stresses. By understanding the molecular mechanisms governing vascular sympathetic innervation, therapies may be developed that would allow for the repair of peripheral vascular sympathetic nerve patterning and therefore allow patients to regain normal function.

描述（由申请人提供）：交感神经系统通过改变外周血管阻力来调节血压。交感神经通常支配主要供血动脉并延伸穿过毛细血管前小动脉网络，但不进入毛细血管、小静脉或集合静脉。在发育过程中，当神经元接近并支配靶器官时，轴突延伸紧密跟随动脉。这种与血管的紧密接近表明血管衍生的分子可能在轴突生长和目标神经支配中发挥作用。由于毛细血管前的选择性交感神经支配，我们的假设是，存在可以促进动脉和神经元之间的化学吸引或静脉和神经元之间的化学排斥的分子线索，并且可能由血管细胞表达。我们的具体目标旨在使我们能够识别可能驱动选择性血管交感神经支配的候选分子并评估其体外功能。我们将（1）通过免疫荧光表征胚胎晚期和出生后动物的几条血管中的交感神经支配模式和突触形成，（2）对受神经支配和非神经支配的血管进行消减杂交，以生成差异表达的候选分子列表并验证通过蛋白质印迹和免疫荧光分析它们的表达，(3) 使用颈上神经节外植体，使用三维 (3-D) 共培养模型评估任何已识别候选分子的功能影响与受神经支配和非受神经支配的血管片段一起评估定向神经突生长，以响应将已识别的候选分子应用于培养基。相关性：血管交感神经的改变与高血压（神经过度支配）和心脏移植后的病理性后遗症（去神经支配）等疾病有关。例如，移植后交感神经元的丧失会损害调节外周血流以及充分耐受运动、温度波动和其他身体压力的能力。通过了解控制血管交感神经支配的分子机制，可以开发出能够修复周围血管交感神经模式的疗法，从而使患者恢复正常功能。