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EFFECT OF DENERVATION ON THE FUNCTION OF THE AIRWAYS

去神经支配对气道功能的影响

基本信息

批准号：
7011909
负责人：
Julio PEREZ FONTAN
金额：
$ 18.23万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-04-01 至 2006-03-31
项目状态：
已结题

项目摘要

The nervous system modulates the responses of the airways to inflammatory stimuli. The studies described here continue ongoing research into the role of substance P and other preprotachykinin (PPT)-A gene-encoded tachykinins in this modulation. The proposed work applies genetically altered murine systems to: 1. define the topographical organization and hierarchical connectivity of the airway's peptidergic sensory-motor network, 2. identify the cellular origin of the PPT-A tachykinins released in response to inflammatory stimuli and elucidate the contribution of three candidate cell types (sensory neurons, intrinsic ganglia, or hemopoietic cells) to the ensuing injury, and 3. establish whether over-expression of the PPT-A gene can in itself produce an inflammatory injury or requires a separate inflammatory stimulus. Aim 1 will be accomplished by examining the expression of a fluorescent protein (ECFP) placed under the transcriptional control of the PPT-A 5' regulatory region in conjunction with tracking studies using pseudorabies virus as a retrograde trans-synaptic marker. Aim 2 will be approached by a combination of selective chemical ablation of C-fibers by capsaicin and bone marrow reconstitution experiments in wild type mice and mice homozygous for targeted disruptions of the PPT-A and NK-1 receptor genes. The effects of these manipulations will then be compared in intact, inflamed (immune complex, Sendai virus, and stretch-induced), and denervated airways (selective C-fiber ablation and heterotopic tracheal transplantation). Aim 3 will be achieved by analyzing the effects of transgenic manipulations of the PPT-A gene resulting either in ectopic constitutive overexpression of PPT-A in airway epithelial cells or in isotopic inducible over-expression of PPT-A in intact and inflamed airways (see above). Completion of these aims will improve our understanding of airway neurogenic injury and may help to develop therapeutic strategies to minimize tachykinin amplification of immune-mediated inflammation of the lungs and airways in disease processes such as bronchiolitis obliterans after lung transplantation or hyperoxic/stretch injury after mechanical ventilation.

神经系统调节呼吸道对炎症刺激的反应。本文所述的研究继续了对P物质和其他前速激肽(PPT)-A基因编码的速激肽在这种调节中的作用的研究。拟议的工作适用于转基因小鼠系统：1；定义气道的多肽感觉-运动网络的地形组织和层次连接，2。2 .确定在炎症刺激下释放的PPT-A速激素的细胞起源，并阐明三种候选细胞类型（感觉神经元、内在神经节或造血细胞）对随后的损伤的贡献；确定是否过表达的PPT-A基因本身可以产生炎症损伤或需要一个单独的炎症刺激。目的1将通过检查置于ppt - a5 '调控区转录控制下的荧光蛋白（ECFP）的表达，并结合使用伪狂犬病毒作为逆行反式突触标记物的跟踪研究来完成。目标2将通过辣椒素选择性化学消融c纤维和野生型小鼠和纯合子小鼠的骨髓重建实验来实现，以靶向破坏PPT-A和NK-1受体基因。然后比较这些操作在完整、炎症（免疫复合物、仙台病毒和拉伸诱导）和失神经气道（选择性c纤维消融和异位气管移植）中的效果。目的3将通过分析对PPT-A基因的转基因操作的影响来实现，这些操作会导致气道上皮细胞中PPT-A的异位组成性过表达，或者在完整和发炎的气道中同位素诱导的PPT-A过表达（见上文）。这些目标的完成将提高我们对气道神经源性损伤的理解，并可能有助于制定治疗策略，以最大限度地减少肺和气道疾病过程中免疫介导炎症的速激肽扩增，如肺移植后闭塞性细支气管炎或机械通气后高氧/拉伸损伤。