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求助基金摘要一篇：哮喘模型大鼠气道迷走中枢去抑制的机制及胞外核苷酸代谢和调节异常
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求助基金摘要一篇：哮喘模型大鼠气道迷走中枢去抑制的机制及胞外核苷酸代谢和调节异常在其中的作用！ |
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sweeticeman
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2楼2018-08-19 08:35:29
wangjijiang
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哮喘是慢性气道炎性疾病,伴紧张和反射性气道迷走神经活动增强。严重发作时,气道迷走神经活动呈与炎症程度无关的持续紧张,但中枢机制不明;吸入糖皮质激素结合β2肾上腺素受体激动剂疗效很差,但抗胆碱药能有效控制。在哮喘大鼠气道迷走中枢,我们前期发现小胶质细胞(MG)被激活,在本项目进一步假设这种MG激活以M2型为主,且其分泌的BDNF通过激活神经元上的TrkB受体,上调1型Na+-K+-2Cl-同向转运体,下调2型K+-Cl-同向转运体,使神经元对抑制性神经递质的反应减弱甚至反转为兴奋,发生去抑制。ATP是重要的MG激活物质。我们假设哮喘时MG激活由外核苷酸酶CD39和CD73表达下调、嘌呤能P2X4型受体上调并激活所介导。拟用ELISA,免疫组化,western-blot,RT-PCR,膜片钳,shRNA干扰和肺功能分析等方法予以验证,以期揭示严重哮喘时气道迷走神经紧张性增强的机制并发现新疗法。 Asthma is a chronic inflammatory airway disease with augmented tonic and reflex airway vagal activity. In its lethal attack, airway vagal tone is exaggerated and persistent even without consistent severe airway inflammation; inhalation of glucocorticoids and application of β2-adrenergic agonists are poorly effective whereas assistant anti-cholinergic agents are satisfactory in its control. The central mechanisms of exaggerated airway vagal tone in lethal asthma attack are unknown. In our preliminary study, microglia were found to be activated in the sensory relay center [the nucleus tractus solitarius (NTS)] and airway vagal efferent centers. In this proposal, we hypothesize that microglia in airway vagal centers are alternatively and predominantly polarized to their M2 type releasing brain-derived neurotrophic factor (BDNF), which, via activation of its TrkB receptors in airway vagal preganglionic neurons (AVPNs), causes up-regulation of Na+-K+-2Cl- co-transporter 1 (NKCC1) and down-regulation of K+-Cl- co-transporter 2 (KCC2) in these neurons, leading to weakened or reversed response of them to inhibitory neurotransmitters, and consequently enhances airway vagal tone. Since ATP plays an important role in the activation of microglia, we further hypothesize that the polarization of microglia in the air vagal centers of asthmatics is mediated by down-regulation of ectonucleotidases CD39 and CD73, and upregulation and activation of purinergic P2X4 receptors (P2X4R). ELISA, imunohistochemical staining, western-blot, RT-PCR, patch-clamp, shRNA interference and pulmonary function analysis are to be used to test these hypotheses. Execution of this project is significant for revealing the central mechanisms of enhanced airway vagal tone in lethal asthma attack and for discovery of new anti-asthma therapy. |
3楼2022-08-17 17:02:49