GLCCI1应答糖皮质激素效应调控哮喘小鼠肾上腺髓质嗜铬细胞转分化的表观遗传学机制

The normal phenotype of adrenal medullary chromaffin cell (AMCC) was determined by the superiority status of glucocorticoids. Some scientists reported that a functional variant of glucocorticoid-induced transcript 1 gene (GLCCI1) was associated with substantial decrements in the response to glucocorticoids in patients with asthma. Recently, we found that asthma during the pregnancy of rat dams promotes asthma susceptibility in their offspring, and that the declined epinephrine induced by the transformation from AMCC to neuron plays an important role in this process. It is suggested that the variants of structure and expression in GLCCI1 down-regulate the biological role of glucocorticoid, which will induce the transition from AMCC to neuron under the stimulation of nerve growth factor; furthermore, the offspring can acquire the cellular transition via pregnancy. In order to certify the view above, we intend to observe the relationship between the variants of GLCCI1 and the function of AMCC in asthma patients, and explore the weaken effects of glucocorticoid on the phenotype of AMCC regulated by GLCCI1 in asthma, then to clarify the effects of the variants of GLCCI1 in pregnancy asthma on the phenotype of AMCC in offspring,which provides a potiental target for the treatment of asthma.

肾上腺髓质嗜铬细胞的表型取决于糖皮质激素（GC）的效应状态。糖皮质激素诱导转录-1-基因（GLCCI1）是GC作用链中的关键元件，其基因结构和表达异常能够降低GC效应并影响到子代。我们发现哮喘大鼠所产子代对哮喘的易感性较对照子代增高，其原因与嗜铬细胞发生转分化导致肾上腺素分泌降低有关。据此推测哮喘状态下嗜铬细胞转分化可能归因于GLCCI1基因结构和表达异常进而弱化GC效应所致。为证实上述观点，本项目拟研究：1、明确哮喘患者GLCCI1基因结构和表达变化与嗜铬细胞功能状态的对应关系；2、明确GLCCI1基因结构和表达变化对哮喘小鼠嗜铬细胞表型的影响及其对GC效应的应答机制；3、明确妊娠期哮喘小鼠GLCCI1基因结构和表达异常导致GC效应弱化对子代嗜铬细胞表型的影响及其机制。本项目的完成将为哮喘的早期防控提供可能的作用靶点。

本项目发现：GLCCI1 rs11976862、GLCCI1 rs37972与哮喘的易感性密切关联。与杂合子哮喘患者和野生型纯合子哮喘患者相比，rs11976862、rs37972及rs37973突变型纯合子哮喘患者对糖皮质激素的反应性显著降低。哮喘患者外周血肾上腺素及皮质醇水平与第一秒用力呼气量（FEV1）呈正相关。rs37973突变型纯合子哮喘患者外周血肾上腺素水平及血皮质醇水平显著高于野生型哮喘患者和杂合子哮喘患者。利用GLCCI1基因敲除小鼠构建哮喘模型并用糖皮质激素对其干预，结果发现GLCCI1表达水平与哮喘模型糖皮质激素敏感性之间存在关联，与肾上腺素水平及皮质醇水平变化亦存在关联。