Identification of the growth-promoting PKD/YAP axis as a novel target for the statins in intestinal epithelial cells.

鉴定促生长 PKD/YAP 轴作为肠上皮细胞中他汀类药物的新靶点。

• 批准号: 9752221
• 负责人: JUAN ENRIQUE ROZENGURT
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752221
• 关键词: Agonist; Attention; Biological; Cell Proliferation; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Colon; Colorectal; Colorectal Cancer; DNA biosynthesis; Digestive System Disorders; Drosophila genus; Drug usage; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; FDA approved; Family; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Gastrointestinal Diseases; Gene Expression; Genetic Transcription; Growth; Growth Factor; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Intervention; Intestinal Diseases; Intestinal Mucosa; Intestines; LGR5 gene; Laboratories; Lipids; Mediating; Modeling; Mucous Membrane; Mus; Natural regeneration; Neurotransmitters; Nuclear; Organ Size; Outcome; Pathogenesis; Pathway interactions; Pattern; Peptides; Pharmaceutical Preparations; Phosphorylation; Play; Population; Process; Protein Inhibition; Protein-Serine-Threonine Kinases; Regenerative Medicine; Regulation; Regulator Genes; Role; Signal Transduction; Stem cells; Stimulus; Testing; Therapeutic Intervention; Time; Transcription Coactivator; Veterans; base; carcinogenesis; cell type; in vivo; inhibitor/antagonist; innovation; interest; intestinal homeostasis; migration; novel; novel strategies; prevent; progenitor; programs; protein function; protein kinase D; response; response to injury; stem cell biology; tissue regeneration; transcription factor; tumor progression

The sequential proliferation, lineage-specific differentiation, migration and death of the epithelial cells of the intestinal mucosa is a tightly regulated process modulated by a broad range of regulatory peptides, neurotransmitters, bioactive lipids and differentiation signals. Many of these stimuli act through heptahelical G protein-coupled receptors (GPCRs). Despite their fundamental importance, the intracellular signal transduction mechanisms involved remain incompletely understood. Protein kinase D (PKD) is emerging as a key node in GPCR signaling and consequently the understanding of PKD regulation and function in intestinal epithelial cells is of intense interest and potential impact. The highly conserved Hippo/YAP/TAZ pathway is also attracting strong attention as a key regulator of organ-size, tissue regeneration, carcinogenesis and GPCR signaling. Based on our preliminary results, we identified a novel crosstalk between PKD and YAP that plays a critical role in promoting intestinal epithelial cell proliferation. Further preliminary results demonstrate that FDA-approved statins act as potent inhibitors of GPCR/PKD-induced YAP-induced transcription and DNA synthesis in intestinal epithelial cells. Statins also abrogated enteroid formation in vitro and prevented regeneration of colon mucosa after injury. Consequently, our central hypotheses are: 1) PKD/YAP/TAZ signaling plays a vital role in promoting the proliferation of intestinal epithelial cells including progenitor/stem cells and 2) statins restrain intestinal epithelial cell proliferation by targeting the PKD/YAP/TAZ axis in these cells. An important translational corollary is that the widely used drugs of the statin family provide a novel strategy in the chemoprevention of colorectal (CRC) and IBD-related CRC through inhibition of the growth-promoting PKD/YAP/TAZ axis. Three Specific Aims are proposed: SPECIFIC AIM 1: Identify the mechanism(s) by which the lipid- lowering drugs of the statin family target signaling through the PKD/YAP axis in intestinal epithelial cells; SPECIFIC AIM 2: Characterize the impact of statin-induced inhibition of the PKD/YAP/TEAD pathway on the proliferation of intestinal epithelial cells in vivo, including progenitor and Lgr5+ intestinal stem cells and enteroids in 3 D cultures in vitro; SPECIFIC AIM 3: Determine the role of the statin-sensitive PKD/YAP/TEAD axis in intestinal epithelial cell regeneration and carcinogenesis. We anticipate that the outcome of this proposal will provide a robust rationale for implementing innovative therapeutic interventions targeting the PKD/YAP signaling axis in proliferative diseases of the digestive system, including CRC and IBD- associated CRC in US veterans as well as in the US population at large.

上皮细胞的顺序增殖、谱系特异性分化、迁移和死亡