子痫前期是严重的妊娠期疾病，其发病机制十分复杂。我们在前期研究中证实，新型的肿瘤坏死因子超家族成员LIGHT可以诱导孕鼠产生子痫前期的临床表现，包括高血压、蛋白尿和肾组织损伤，但LIGHT在子痫前期中的致病机制尚不清楚。我们进一步发现LIGHT可以诱导抗血管生成因子sFlt-1的生成增多，提示sFlt-1导致的血管生成抑制可能是LIGHT诱导子痫前期的重要作用环节。为明确LIGHT刺激sFlt-1增加的细胞内机制，我们检测了重要的转录因子HIF-1α和剪切辅助因子U2AF65的表达，发现LIGHT可以上调孕鼠胎盘组织HIF-1α和U2AF65的蛋白水平。本课题将在此基础上深入探讨：1 sFlt-1是否是LIGHT诱导子痫前期的关键下游因子；2 LIGHT是否通过刺激HIF-1α在转录水平上调控sFlt-1的表达；3 LIGHT是否通过刺激U2AF65在转录后修饰上调控sFlt-1的表达。

Preeclampsia (PE) is a life-threatening hypertensive renal disorder of pregnancy. The current treatment for PE is limited because the underlying mechanisms of PE remain undefined. However, recent research has indicated that PE is associated with abnormal immune response. LIGHT (TNFSF14) is a novel Tumor Necrosis Factor Superfamily member which plays a key role in multiple immune related diseases. Our preliminary studies have demonstrated LIGHT can induce PE features include hypertension, proteinuria and glomerular endotheliosis. Both in vivo and in vitro experiments have shown Soluble fms-like tyrosine kinase 1 (sFlt-1), a well recognized anti-angiogenic factor, is elevated in LIGHT induced PE. However, molecular basis underlying its up-regulation by LIGHT remains unclear. We found that hypoxia inducible factor-1α (HIF-1α), an important transcriptional factor, and U2AF65, a key molecule involved in alternative splicing, are significantly increased in the placentas of LIGHT-treated pregnant mice. Based on these findings we hypothesis: 1. sFlt-1 is a crucial downstream molecule mediates the biological functions of LIGHT in PE; 2. LIGHT, signal through HIF-1α, can un-regulate sFlt-1 expression via transcriptional modification; 3. LIGHT, signal through U2FA65, can un-regulate sFlt-1 expression via post-transcriptional modification.