α1B肾上腺素受体调控细胞核F-actin形成在电离辐射造血干细胞DNA损伤修复中的作用与机制研究

储备长期存活造血干细胞（rLT-HSCs）是放射损伤骨髓造血功能重建的基础，其DNA损伤修复与RASSF1A/MRTF-A-SRF通路介导的细胞核F-actin形成密切相关，而RASSF1A又受NADPH氧化酶（NOXs）来源的活性氧（ROS）调控。已知，α1B肾上腺素受体在辐射造血功能重建中发挥重要调控作用，但机制不清。我们前期发现，α1B受体阻断不仅会影响NOXs活性和RASSF1A表达，还会抑制DNA损伤修复，推测α1B受体可能通过调控NOXs来源的ROS而影响RASSF1A/MRTF-A-SRF通路活化。本项目拟采用α1B和RASSF1A两种条件性敲除小鼠，分析辐照该通路活化，NOXs来源的ROS水平和细胞核F-actin形成变化，揭示α1B受体调控rLT-HSCs DNA损伤修复的关键机制，并观察调控α1B受体及关键通路活性对辐照骨髓造血功能重建的影响，为放射损伤救治寻找新思路。

Reserve long-term hematopoietic stem cells (rLT-HSCs) is the key for hematopoietic reconstitution after radiation injury. Their DNA damage repair is closely related to RASSF1A/MRTF-A-SRF pathway-mediated nuclear F-actin, and the expression of RASSF1A is regulated by reactive oxygen species (ROS) derived from NADPH oxidases (NOXs). Previous studies reported that α1B adrenoceptor plays an important role in the regulation of hematopoietic reconstitution after radiation, however, its mechanism has not been fully elucidated. In our preliminary experiments, we has found that the blockade of the α1B adrenoceptor not only affects NOXs activity and RASSF1A expression, but also inhibits DNA repair after radiation. Therefore, we speculate that the α1B receptor may play an important role in the activation of RASSF1A/MRTF-A/SRF pathway via the regulation of ROS from NOXs. In this regard, we intend to investigate the activation of this pathway, ROS level derived from NOXs and nuclear F-actin to reveal the crucial mechanism of α1B adrenoceptor in regulating rLT-HSCs DNA repair with α1B and RASSF1A conditional knockout mice, and then investigate the influence on hematopoietic construction through the regulation of α1 adrenoceptor and the activity of this crucial pathway post radiation exposure，which aims to find new ideas for the treatment of radiation injury.