Hippo在激素调控的昆虫组织凋亡重建中的功能及作用机理

The Hippo signaling pathway is highly conserved and limits organ size by restricting cell proliferation and by promoting apoptosis. In addition，the Hippo pathway has a critical role in the self-renewal and expansion of stem cells and tissue-specific progenitor cells, and has important functions in tissue regeneration. Although the core of the signaling pathway is well understood,the up stream inputs and the downstream transcriptional regulation are still obscure to us. Metamorphosis is a hormone regulated process by which holometabolous insects are transformed from larva, to pupa, and to adult. The larval components are degraded, and the adult proteins and tissues are formed during the process. Therefore metamorphosis of insects provides a model to explore the mechanism of Hippo pathway. Here we intend to knock down Hippo in lepidopteran insects Helicoverpa armigera to determine whether the process of metamorphosis is the downstream regulated target of Hippo.Furthermore,we explore the mechanism of Hippo in apoptosis and remodeling, and research the regulation of hormone signal transduction pathway on Hippo in transcription, translation and post-translation level.

Hippo途径是一个保守的信号途径，在发育过程中通过限制细胞增殖和促进凋亡来控制器官尺寸。此外，它还通过调控干细胞分化和自我更新在组织再生中发挥作用。其核心机制已经比较清楚,但其下游转录调控靶标及上游信号输入尚不清楚。变态是昆虫从幼虫经蛹发育为成虫的过程，此过程包含激素信号调控下的幼虫组织凋亡和成虫组织通过细胞增殖分化而完成的重建，这为Hippo途径分子机理的完善提供了很好的研究模型。本研究中，我们拟以鳞翅目昆虫棉铃虫为材料，干扰Hippo确定昆虫变态时期组织凋亡重建是否是Hippo途径的下游调控靶标并研究其调控机理。通过干扰或过表达的方法，研究Hippo对激素信号有无应答并探讨其与激素信号转导途径关键因子在转录、翻译及翻译后水平上的相互作用。最终阐明Hippo在激素调控的变态时期组织凋亡重建中的功能及作用机理。

在昆虫变态发育过程中，细胞程序性死亡受到蜕皮激素和Hippo信号的协同调控，但两者之间的相互作用尚不清楚。本研究提供证据证明，蜕皮激素通过上调Hippo转录来促进细胞程序性死亡，从而诱导变态的发生。首先，我们发现Hippo通过诱导凋亡执行基因caspase的活性来参与蜕皮激素诱导的变态。然后我们发现蜕皮激素通过ecdysone receptor (EcR), ultraspiracle protein (USP) 和 hormone receptor 3 (HR3)等转录因子在转录水平上调Hippo的表达。同时Hippo信号途径对HR3还有负反馈调节。综上，本研究鉴定蜕皮激素为Hippo途径的一种新的输入信号，同时蜕皮激素信号途径关键因子HR3又是Hippo途径的直接调控靶标，从而把两种信号途径联系在一起。它们协同调控细胞程序性死亡从而调控昆虫变态发育。