宫内生长迟缓致成年期哮喘的表观遗传调控机制

There is a wealth of epidemiological evidence that intrauterine growth retardation (IUGR) or lower birth weight is strongly correlated with an increased risk of asthma later in life. Moreover, epigenetics plays an important role in the fetal origins of adult disease. Hence, we propose a hypothesis that IUGR could induce epigenetic modification of asthma-related genes and could be maintained throughout the life; these epigenetic changes would induce IUGR individuals to be highly sensitive to allergens, leading to the occurrence of asthma; and early intervention could reduce the risk of IUGR-related asthma later in life. In the present study, we will investigate the role of epigenetic regulation in IUGR-related asthma in adulthood, and further investigate whether the appropriate interventions in the early stage of IUGR individuals might decrease the risk of asthma in later life. We also will explore whether the specific epigenetic changes of peripheral blood leukocyte might be used as a biological marker to predict asthma risk. The present study would elucidate the epigenetic mechanisms of the fetal origins of adult disease, and reveal the phenomenon that the early appropriate intervention could reduce the risk of asthma in later life. The study would provide new insights in the prevention and treatment of asthma in childhood or adulthood, and provide a new theoretical basis for controlling the fetal origins of adult disease, which could have an important clinical significance.

本课题针对宫内生长迟缓（IUGR）的个体在成年后有发生哮喘的风险，结合前期发现表观遗传调控在胎儿来源的成人疾病中的作用，首次提出IUGR可能诱导哮喘相关基因的表观遗传修饰并可以持续存在，并使IUGR个体在生命后期对过敏原等刺激异常敏感从而导致哮喘的发生，而且早期干预可以降低IUGR成年后发生哮喘风险的假设。本课题探讨表观调控机制在IUGR诱导的成年期哮喘中的作用，同时亦探讨在个体发育早期阶段给予适当的干预措施能否降低生命后期哮喘的风险，外周血白细胞特定的表观遗传变化能否作为预测哮喘的一个生物标记。本研究对阐明胎儿来源的成人疾病的表观遗传机制，以及早期适当的干预能够降低生命后期哮喘的风险具有重要意义。可望为儿童和成人哮喘的预防和治疗提供新的思路，并为胎儿来源的成人疾病控制提供新的理论依据，有十分重要的临床意义。

流行病学研究已经揭示宫内生长迟缓（IUGR）或低出生体重个体在成年后有发生哮喘的风险，然而确切的机制尚未明了。结合前期发现表观遗传调控在胎儿来源的成人疾病中的作用，提出IUGR可能诱导哮喘相关基因的表观遗传修饰并可以持续存在，并使IUGR个体在生命后期对过敏源等刺激异常敏感从而导致哮喘的发生。在目前的项目中，我们发现母亲孕期营养限制可引起新生大鼠肺组织哮喘相关基因启动子区域组蛋白乙酰化水平明显增加，但DNA甲基化无明显改变，这些变化导致了成年后对过敏原等刺激异常敏感，导致更加显著的哮喘改变。而外周血白细胞相关基因的表观变化可以部分反映肺组织的的表观变化，因此可作为哮喘风险评估的预测指标。本研究为儿童和成人哮喘的预防和治疗提供新的思路，并为胎儿来源的成人疾病控制提供新的理论依据，有十分重要的临床意义。