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.

上皮的顺序增殖，谱系特异性分化，迁移和死亡 肠粘膜细胞是一个严格调节的过程，该过程由广泛范围 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Heptahelical G蛋白偶联受体（GPCR）起作用。尽管他们 基本重要性，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）作为GPCR信号中的关键节点出现 因此，理解PKD调节和肠上皮细胞功能 具有强烈的兴趣和潜在影响。高度保守的河马/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的关注， 致癌和GPCR信号传导。基于我们的初步结果，我们确定了一个小说 PKD和YAP之间的串扰在促进肠上皮细胞中起着至关重要的作用 增殖。进一步的初步结果表明，FDA批准的他汀类药物是有效的 GPCR/PKD诱导的YAP诱导的转录和DNA合成的抑制剂 上皮细胞。他汀类药物还废除了体外的肠片形成，并阻止了 受伤后结肠粘膜。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的增殖中起着至关重要的作用 祖细胞/干细胞和2）他汀类药物通过靶向限制肠上皮细胞增殖 这些细胞中的PKD/YAP/TAZ轴。一个重要的翻译推论是广泛使用的 他汀类药物的药物为结直肠化化学预防提供了新的策略（CRC） 通过抑制促进生长的PKD/YAP/TAZ轴，与IBD相关的CRC。三 提出了具体目的：具体目的1：确定脂质的机制 通过肠道中的PKD/YAP轴降低他汀类药物靶标信号的药物 上皮细胞；特定目标2：表征他汀类药物诱导的抑制作用的影响 PKD/YAP/TEAD途径在体内肠上皮细胞的增殖上，包括 祖细胞和LGR5+肠干细胞和肠道细胞在体外3 d培养物中；具体目标 3：确定肠上皮细胞中他汀类药物敏感的PKD/yap/tead轴的作用 再生和癌变。我们预计该提议的结果将提供 实施针对PKD/YAP的创新治疗干预措施的强大理由 消化系统增殖性疾病中的信号轴，包括CRC和IBD- 美国退伍军人以及整个美国人口的相关CRC。