Systems-level role of GSK3 in colonic epithelium homeostasis and drug resistance

GSK3 在结肠上皮稳态和耐药性中的系统水平作用

• 批准号: 9204413
• 负责人: STEVEN J ALTSCHULER
• 金额: $ 31.3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204413
• 关键词: 3-Dimensional; Affect; Behavior; Biological Assay; Biological Models; Categories; Cell Culture Techniques; Cell Fate Control; Cell physiology; Cells; Clinical Trials; Complex; Crohn' s disease; Cues; Disease; Drug Targeting; Drug effect disorder; Drug resistance; Epithelial; Epithelial Cells; Epithelium; FDA approved; Future; Genetic; Glycogen Synthase Kinase 3; Goals; Homeostasis; Human; Image; Individual; Intestines; Irritable Bowel Syndrome; Life; Maintenance; Malignant neoplasm of gastrointestinal tract; Mediating; Modeling; Molecular; Monitor; Organoids; Output; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Physiological; Reporter; Role; Signal Pathway; Signal Transduction; Specificity; Stem cells; System; Tissues; Tyrosine Kinase Inhibitor; Ulcerative Colitis; base; cell type; gastrointestinal epithelium; high dimensionality; innovation; intestinal epithelium; kinase inhibitor; notch protein; prototype; public health relevance; response; self-renewal; stem cell niche; stemness; tool

DESCRIPTION (provided by applicant): Self-renewing intestinal epithelium requires layers of precise control for homeostasis. Amazingly, intestinal epithelium completely renews itself every five days, with multiple cell types maintained at just the right ratios throughout an individual's entire life. However, our understanding of how epithelium maintains such robust organization is far from complete. Lack of this exquisite homeostatic control is the basis for a variety of diseases, including Crohn's disease, irritable bowel syndrome, ulcerative colitis, and gastrointestinal cancers. GSK-3 is a quintessential signaling hub in intestinal tissue homeostasis: it receives and deciphers multiple upstream microenvironmental signals, selectively affects multiple downstream cellular processes, and alters cellular response to drugs. Despite GSK-3's presence in many cellular processes, its function remains unclear and understudied. We lack a systematic understanding of when and where GSK-3 affects the cascade of signals from the microenvironment through molecular networks to cellular decisions in the context of complex epithelial tissues. Here, we propose to study the role of GSK-3 as a hub for signal transduction and maintenance of tissue homeostasis as well as identify drug classes whose effects depend on GSK-3 activities in physiologically relevant conditions. To accomplish this, we have developed: innovative organotypic models of gut epithelium that are ideal for image-based perturbation assays; live-cell reporters of GSK-3 activity; and quantitative, single-cell approaches for deciphering GSK-3's role in transforming microenvironmental signals to homeostatic decisions. Together, we propose to: (Aim 1) identify GSK-3 interaction networks that regulate gut homeostasis; (Aim 2) understand GSK-3's role in signal insulation and crosstalk; and (Aim 3) elucidate how GSK-3 activity affects drug response.

描述（由申请人提供）：自我更新肠上皮需要精确控制稳态的层。令人惊讶的是，肠上皮每五天完全更新一次，多种细胞类型在整个人的一生中保持正确的比例。但是，我们对上皮如何维持这种健壮组织的理解远非完整。缺乏这种精致的稳态控制是多种疾病的基础，包括克罗恩病，肠易激综合症，溃疡性结肠炎和胃肠道癌。 GSK-3是肠道组织稳态中的典型信号枢纽：它接收并解密多个上游上游微环境信号，有选择地影响多个下游细胞过程，并改变了细胞对药物的反应。尽管GSK-3在许多细胞过程中的存在，但其功能仍未清楚和研究。我们缺乏对GSK-3何时何地影响在复杂的上皮组织的背景下从微环境到细胞决策的何时何地影响GSK-3的何时何地影响信号的级联。在这里，我们建议研究GSK-3作为组织稳态的信号转导和维持的枢纽的作用，并识别出依赖于GSK-3在生理相关条件下的GSK-3活性的药物类别。为了实现这一目标，我们已经开发了：肠道上皮的创新器官模型，非常适合基于图像的扰动测定； GSK-3活动的活细胞记者；和定量， 单细胞的方法是破译GSK-3在将微环境信号转换为稳态决策中的作用。我们一起建议：（目标1）确定调节肠内稳态的GSK-3相互作用网络； （AIM 2）了解GSK-3在信号绝缘和串扰中的作用； （AIM 3）阐明GSK-3活性如何影响药物反应。