Conserved mechanisms in epithelial niche regulation of intestinal stem cells

项目摘要 这项建议的目标是剖析道和道的潜在机制。 在两种果蝇中介导机械感觉和组织生长的Ste20激酶亚家族 和老鼠的肠子。人类胃肠道(GI)上皮中的数十亿细胞 每天都换新换新。这种快速的细胞替换速度也允许肠道 提供适应性生长，在此期间，上皮可以根据 这种需要。然而，对人胃肠道上皮组织动态平衡的机制研究是， 相当困难，因为涉及的细胞类型、途径和微生物的复杂性。这个 果蝇中肠与哺乳动物有相似但更简单的解剖学和生理学 肠子。具有高度细胞特异性的标记和先进的遗传技术，如 以及短暂的生命周期，允许进行多代的体内实验，果蝇 中肠已经成为研究复杂肠道生物学的一个非常有价值的系统。我们有 最近发现了果蝇Ste20激酶畸形蛋白的一种新功能，它可以调节 食物颗粒的摄入引起机械拉伸信号来调节生长。另一个Ste20 激酶Tao在上游发挥作用，并可能将膜机械传感元件连接到 畸形和下游增长信号。这一途径在哺乳动物中非常保守， 畸形蛋白(MINK1、MAP4K4和tnik)的同源物，以及其他Ste20激酶，包括 河马(MST1和MST2)类似地可以与下游组件LATS和 是啊。然而，对这些哺乳动物同源物的功能分析存在很强的障碍，因为 到高度重叠的职能。因此，《诗经》中对道的补充研究 果蝇中肠和小鼠肠道中的TAOK1/2将提供更好的理解 这种保守的途径介导机械感觉影响肠道组织的生长。这款车 有生理上的相关性，因为人类患者从肠切除中恢复，减肥 手术或放射治疗在摄入固体食物后有更好的肠道生长。同时， 全肠外营养，即只通过静脉供应，会引起肠粘膜 萎缩。因此，固体食物和肠道上皮之间的相互作用是有益的，但 机制还不是很清楚。果蝇中肠和小鼠的遗传学研究 肠道，随后的分子和蛋白质-蛋白质相互作用分析将揭示它们的 TAO通路在传递机械信号促进适应性生长中的作用 并应该为人类肠道中类似的过程提供重要的见解。

Project Summary The goal of this proposal is to dissect the underlying mechanism of the Tao and TAOK subfamily of Ste20 kinases in mediating mechanosensing and tissue growth in both Drosophila and mouse intestines. Billions of cells in the human gastrointestinal (GI) tract epithelium are shed and replaced every day. This fast pace of cell replacement also allows the intestine to afford adaptive growth, during which the epithelium can expand or shrink rapidly according to the need. Mechanistic study of tissue homeostasis in the human GI tract epithelium is, however, rather difficult because of the complexity of cell types, pathways and microbes involved. The Drosophila midgut has a similar but yet simpler anatomy and physiology than mammalian intestines. With highly cell-specific markers and sophisticated genetic techniques available, as well as a short life cycle to allow multiple generations of in vivo experiments, the Drosophila midgut has become a highly valuable system to study complex intestinal biology. We have recently discovered a novel function of the Drosophila Ste20 kinase Misshapen that mediates food particle ingestion caused mechanical stretching signal to regulate growth. Another Ste20 kinase Tao functions upstream, and may link the membrane mechanosensing components to Misshapen and downstream growth signaling. This pathway is well-conserved in mammals, with homologs of Misshapen (MINK1, MAP4K4, and TNIK), as well as other Ste20 kinases including Hippo (MST1 andMST2), can similarly interact with the downstream components LATS and YAP. The functional analysis of these mammalian homologs, however, post a strong barrier due to the high level of overlapping functions. Therefore, the complementary study of Tao in Drosophila midgut and TAOK1/2 in mouse intestine will provide a better understanding of how this conserved pathway mediate mechanosensing to affect intestinal tissue growth. This model has physiological relevance, because human patients recovering from bowel resection, bariatric surgery or radiation therapy have better intestinal growth after solid food intake. Meanwhile, total parenteral nutrition, that is through intravenous supply only, causes intestinal mucosal atrophy. Therefore, interaction between solid food and intestinal epithelium is beneficial, but the mechanism is not well-understood. The genetic studies in Drosophila midgut and in mouse intestine, followed by molecular and protein-protein interaction analyses will unveil their sequence of action of this Tao pathway in transducing mechanical signals for adaptive growth and should provide important insights into similar processes in human intestines.