线粒体钙离子信号对果蝇肠道干细胞的增殖调控

Stem cell activity is essential for tissue homeostasis maintenance and regeneration. Stem cell proliferation/differentiation regulation is controlled by micro-environment (niche) and intracellular signals. How these signals are integrated remains elusive. Using Drosophila intestinal stem cell（ISC）as a model, I recently demonstrated that cytosolic Ca2+ can integrate upstream signals and regulate ISC proliferation. ER (Endoplasmic Reticulum) and mitochondria are important cellular Ca2+ storage and function module, which function together to regulate cytosolic Ca2+ signaling timing and effect. It has been shown that stem cells often exploit different metabolic program compared with its differentiated counterpart. In addition, mitochondrial calcium (mitoCa2+) can regulate metabolism. MCU1(mitochondrial calcium uniporter) has recently been identified as the Ca2+ channel in inner mitochondrial membrane. Our preliminary results indicated that mitoCa2+ and ISC activity is controlled by MCU1. Further analyze organellar calcium regulation network and decode the role of mitochondrial calcium on metabolic control of ISC activity would shed new light on mechanism(s) of stem cell fate determination.

干细胞干性维持和增殖受细胞外微环境（niche）和胞内信号的协同调节。但干细胞如何整合这些胞内外信号并做出应答，其机制还不很清楚。本课题组最近NATURE成果表明胞浆钙离子能整合上游信号，经CaN/CRTC通路调控果蝇肠道干细胞（ISCs）增殖。线粒体是钙离子的另一个重要作用中心。钙离子调节线粒体的糖脂代谢和能量生成等，但能否调控干细胞增殖还不清楚。本课题拟以果蝇ISCs为模型研究线粒体钙离子对干细胞代谢和增殖的调控。结合双光子活体成像和分子遗传技术，本课题初步结果表明果蝇ISCs中线粒体钙离子浓度受保守的线粒体钙离子单向转运体（MCU1）调控，而且线粒体钙离子与干细胞活性正相关。本课题将利用活体成像技术进一步研究ISCs内胞浆、线粒体、内质网等细胞器钙离子互作网络，揭示线粒体钙离子调控干细胞代谢和增殖的下游信号通路。本研究将有助于阐明细胞器离子信号及代谢重塑在干细胞命运调控中的分子机制。

成体干细胞对组织稳态和功能维持至关重要。干细胞的增殖和分化受周围微环境（Niche）和胞内信号的协同调节。干细胞如何对这些信号进行整合和应答，其机制还不是很清楚。我最近成果表明胞浆钙离子能整合上游信号通过CRTC/CREB信号调控果蝇肠道干细胞（ISCs）增殖。围绕着这一方向，在项目的资助下，为阐明其调控干细胞增殖的下游靶基因，我们对过表达CRTC的肠上皮细胞进行了转录组测序，发现抗氧化基因和调控蛋白稳态相关的基因显著上调。首次阐明了CRTC 通过蛋白稳态调控干细胞增殖分化中的作用；另外，我们发现核受体调节胰岛α细胞PTL的转录进而影响肠脂代谢的新机制，为肥胖等代谢相关疾病的治疗提供了新的靶点；们同时构建了一种新型的药物筛选体系，为成体果蝇的大规模药物筛选提供了全新的技术平台。