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.

上皮细胞的连续增殖、谱系特异性分化、迁移和死亡 肠粘膜细胞是一个受到广泛调节的严格调节过程 调节肽、神经递质、生物活性脂质和分化信号。其中许多 刺激通过七螺旋 G 蛋白偶联受体 (GPCR) 起作用。尽管他们的 至关重要的是，所涉及的细胞内信号转导机制仍然存在 不完全理解。蛋白激酶 D (PKD) 正在成为 GPCR 信号传导的关键节点 从而了解肠上皮细胞中 PKD 的调节和功能 具有强烈的兴趣和潜在的影响。高度保守的 Hippo/YAP/TAZ 途径是 作为器官大小、组织再生的关键调节剂，也引起了强烈关注， 致癌作用和 GPCR 信号传导。根据我们的初步结果，我们确定了一种新颖的 PKD 和 YAP 之间的串扰对促进肠上皮细胞发挥关键作用 增殖。进一步的初步结果表明 FDA 批准的他汀类药物可作为有效的药物 GPCR/PKD 诱导的 YAP 诱导的肠道转录和 DNA 合成的抑制剂 上皮细胞。他汀类药物还可以在体外消除肠样物质的形成并阻止肠样物质的再生。 损伤后的结肠粘膜。因此，我们的中心假设是：1) PKD/YAP/TAZ 信号传导在促进肠上皮细胞增殖中起着至关重要的作用，包括 祖细胞/干细胞和 2) 他汀类药物通过靶向抑制肠上皮细胞增殖 这些细胞中的 PKD/YAP/TAZ 轴。一个重要的翻译推论是广泛使用 他汀类药物为结直肠癌 (CRC) 的化学预防提供了新策略 通过抑制促进生长的 PKD/YAP/TAZ 轴来抑制 IBD 相关的 CRC。三 提出了具体目标： 具体目标 1：确定脂质- 降低他汀类药物家族通过肠道 PKD/YAP 轴靶向信号传导 上皮细胞；具体目标 2：描述他汀类药物诱导的抑制作用的影响 PKD/YAP/TEAD通路对体内肠上皮细胞增殖的影响，包括 体外 3D 培养物中的祖细胞和 Lgr5+ 肠道干细胞和肠样细胞；具体目标 3：确定他汀类药物敏感的PKD/YAP/TEAD轴在肠上皮细胞中的作用 再生和癌变。我们预计该提案的结果将提供 针对 PKD/YAP 实施创新治疗干预措施的有力理由 消化系统增殖性疾病（包括结直肠癌和炎症性肠病）中的信号轴 美国退伍军人以及美国广大民众中存在相关的结直肠癌。