Conserved mechanisms in epithelial niche regulation of intestinal stem cells

肠干细胞上皮生态位调节的保守机制

• 批准号: 10598633
• 负责人: Y. Tony Ip
• 金额: $ 40.8万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-17 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598633
• 关键词: Adult; Affect; Anatomy; Atrophic; Biological Assay; Biology; Cells; Complement; Complex; Cultured Cells; Drosophila genus; EGF gene; Eating; Epithelial Cells; Epithelium; Excision; Experimental Genetics; Food; Gastrointestinal Diseases; Gastrointestinal tract structure; Generations; Genetic; Genetic Models; Genetic Techniques; Genetic study; Goals; Growth; Homeostasis; Homologous Gene; Human; Immune response; Individual; Inflammatory Bowel Diseases; Ingestion; Intestinal Mucosa; Intestines; Intravenous; Ion Channel; Knock-in; Knock-out; Life Cycle Stages; Link; MAP4K4 gene; Malignant Neoplasms; Mammals; Mechanics; Mediating; Membrane; Metabolic Control; Microbe; Midgut; Modeling; Molecular; Mus; Operative Surgical Procedures; Organ; Pathologic; Pathway interactions; Patients; Personal Satisfaction; Phenotype; Phosphotransferases; Physiological; Physiology; Process; Proliferating; Proteins; Radiation therapy; Regulation; Signal Transduction; Small Intestines; Solid; Stomach; Stretching; Supporting Cell; System; Therapeutic; Tissues; Total Parenteral Nutrition; Transcription Coactivator; bariatric surgery; cell type; conditional knockout; experimental study; flexibility; in vivo; insight; intestinal epithelium; knockout gene; mechanical signal; mechanotransduction; model organism; novel; nutrient absorption; particle; precursor cell; protein protein interaction; repaired; response; stem cell proliferation; stem cells; tissue regeneration; tissue stem cells; tool; treatment strategy

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.

项目总结

项目成果

Enteroendocrine cells support intestinal stem-cell-mediated homeostasis in Drosophila.

• DOI: 10.1016/j.celrep.2014.08.052
• 发表时间: 2014-10-09
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Amcheslavsky A;Song W;Li Q;Nie Y;Bragatto I;Ferrandon D;Perrimon N;Ip YT
• 通讯作者: Ip YT

YAP/TAZ and Hedgehog Coordinate Growth and Patterning in Gastrointestinal Mesenchyme.

• DOI: 10.1016/j.devcel.2017.08.019
• 发表时间: 2017-10-09
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Cotton JL;Li Q;Ma L;Park JS;Wang J;Ou J;Zhu LJ;Ip YT;Johnson RL;Mao J
• 通讯作者: Mao J

YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression.

• DOI: 10.1016/j.celrep.2019.03.021
• 发表时间: 2019-12-03
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Li H;Li Q;Dang K;Ma S;Cotton JL;Yang S;Zhu LJ;Deng AC;Ip YT;Johnson RL;Wu X;Punzo C;Mao J
• 通讯作者: Mao J

Gudu, an Armadillo repeat-containing protein, is required for spermatogenesis in Drosophila.

• DOI: 10.1016/j.gene.2013.08.080
• 发表时间: 2013-12-01
• 期刊: Gene
• 影响因子: 3.5
• 作者: Cheng W;Ip YT;Xu Z
• 通讯作者: Xu Z

Tissue damage-induced intestinal stem cell division in Drosophila.

• DOI: 10.1016/j.stem.2008.10.016
• 发表时间: 2009-01-09
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Amcheslavsky A;Jiang J;Ip YT
• 通讯作者: Ip YT