Conserved mechanisms in epithelial niche regulation of intestinal stem cells

项目摘要 这个提议的目标是剖析道和TAOK的潜在机制 Ste 20激酶亚家族介导果蝇的机械感应和组织生长 和老鼠肠子人胃肠道（GI）上皮细胞中有数十亿个细胞， 每天都要更换。这种快速的细胞替换也使肠道 提供适应性生长，在此期间，上皮细胞可以根据 需求然而，人类胃肠道上皮组织稳态的机制研究， 由于涉及的细胞类型、途径和微生物的复杂性，的 果蝇中肠有一个类似的，但更简单的解剖和生理比哺乳动物 肠随着高度细胞特异性标记和复杂的遗传技术的可用， 果蝇的生命周期短，可以进行多代体内实验， 中肠已经成为研究复杂肠道生物学的非常有价值的系统。我们有 最近发现了果蝇Ste 20激酶Misshapen的一种新功能， 食物颗粒的摄入引起机械拉伸信号来调节生长。另一个Ste 20 激酶Tao在上游起作用，并且可以将膜机械感测组分连接到 畸形和下游生长信号。该途径在哺乳动物中非常保守， Misshapen的同源物（MINK 1、MAP 4K 4和TNIK），以及其他Ste 20激酶，包括 Hippo（MST 1和MST 2）可以类似地与下游组分LATS和 雅普。然而，这些哺乳动物同源物的功能分析存在很大的障碍， 高度重叠的职能。因此， 果蝇中肠和小鼠肠道中的TAOK 1/2将提供更好的理解， 该保守途径介导机械感测以影响肠组织生长。该模型 具有生理相关性，因为人类患者从肠切除术、肥胖治疗 手术或放射治疗在固体食物摄入后具有更好的肠道生长。同时， 全胃肠外营养，即仅通过静脉供应， 萎缩因此，固体食物和肠上皮之间的相互作用是有益的，但 机制不太清楚。果蝇和小鼠中肠的遗传学研究 肠道，其次是分子和蛋白质-蛋白质相互作用分析将揭示其 这一Tao通路在为适应性生长转导机械信号中的作用顺序 并将为人类肠道的类似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.