Hsf4是白内障致病基因，其转录活性障碍导致白内障发生。研究发现Hsf4b的磷酸化修饰调控其转录活性。通过体外实验我们证明，Hsf4b/T472的磷酸化修饰调控Hsf4b与核膜转运蛋白importin β-1/Hsc70复合体的结合，进而调控Hsf4b的核内转运和转录活性。但Hsf4b/T472的磷酸化修饰在整体动物体内是否调控Hsf4b的转录活性，进而调控晶状体发育还不清楚。因此，本课题中我们首先揭示直接调控Hsf4b/T472磷酸化的激酶（MEK6，ERK1/2），进而探究晶状体发育中Hsf4b/T472的磷酸化状态及参与的上游信号通路。同时，构建Hsf4b/T472突变的转基因动物模型，体内实验阐明Hsf4b/T472的磷酸化修饰调控晶状体发育的分子机理。该课题将建立一套体内研究Hsf4b转录活性的动物模型，为靶向防治Hsf4b转录活性下降诱发的白内障提供理论依据和药物筛选平台。

Cataract is the predominant cause of blindness worldwide. It consists of aging cataract and congenital cataract. Aging cataract is mainly associated with peroxidation, while the congenital cataract is closely related to the genetic mutations. Exploration of the molecular mechanism underlying cataract is important for therapeutic prevention of cataract. Hsf4 is a family member of heat shock transcriptional factors that are known to regulate the transcription of heat shock proteins in response to the variety of stresses. Impairment of Hsf4b transcriptional activities e.g. germline mutations, has been reported to be closely associated with the human congenital cataract and aging cataract. However, the signaling pathways that regulate Hsf4b transcriptional activities are not completely understood. Our previous results indicated that Hsf4b transcription activities are tightly regulated by posttranslational phosphorylation. Our in vitro data show that phosphorylation of Hsf4b/T472 can regulate Hsf4b nucleus translocation and transcription activity by interacting with the nuclear membrane transporter protein complex importin β-1/Hsc70. MEK6 is a potential kinase for the phosphorylation of Hsf4b/T472. However, it is still not clear whether this phosphorylation site of Hsf4b participates in the regulation of lens development or aging cataract in vivo. In this grant application, we will: 1. Determine the phosphorylation effects of MEK6 pathways on Hsf4b’ transcription activities; 2. Establish the transgenic mouse and zebrafish models to study the roles of phosphorylation of Hsf4b/T472 on Hsf4b transcriptional activity in vivo and during lens development. Our studying results will demonstrate for the first time the regulatory effects of Hsf4b phosphorylation on cataract formation in vivo.