Circadian Clock and Myc-dependent Regulation of Cellular Transformation

生物钟和细胞转化的 Myc 依赖性调节

基本信息

批准号：
10544733
负责人：
Selma Masri
金额：
$ 58.73万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10544733
关键词：
APC mutation ARNTL gene Acceleration Address Adult Age Behavioral Biological Assay Biological Models Cell Proliferation Cells Circadian Dysregulation Circadian Rhythms Circadian gene expression Clinical Clinical Data Code Colorectal Cancer Colorectal Neoplasms Complex Computer Analysis Coupled DNA Damage Data Death Rate Development Diagnostic Neoplasm Staging Diet Dietary Factors Down-Regulation Eating Environmental Risk Factor Enzymes Epithelial Cells Genes Genetic Genome Genome Stability Genomic Instability Goals High Fat Diet Hormonal Human Incidence Intestinal Polyps Intestines Link Loss of Heterozygosity Malignant Neoplasms Maps Measures Mediating Metabolic Metabolic Pathway Metabolism Modeling Molecular Mus Mutation Oncogenic Organoids Pacemakers Pathogenesis Pathway interactions Patients Periodicity Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Polyps Prevention strategy Proliferating Reporting Research Risk Factors Role Sampling Signal Transduction Sleep Wake Cycle Stress Surveys Survival Rate System TP53 gene Testing The Cancer Genome Atlas Time-restricted feeding Tumor Suppressor Proteins United States WNT Signaling Pathway biobank c-myc Genes cancer diagnosis cancer prevention cancer type cell growth regulation circadian circadian pacemaker circadian regulation colon cancer patients colorectal cancer prevention colorectal cancer treatment dietary dietary control driver mutation early onset early onset colorectal cancer exome sequencing experimental study feeding human data insight interdisciplinary approach intestinal epithelium knock-down lifestyle factors metaplastic cell transformation mouse model novel nutrition older patient pharmacologic reconstitution response stable isotope stemness targeted treatment therapy development transcription factor transcriptome tumorigenesis young adult

APC mutation ARNTL gene Acceleration Address Adult Age Behavioral Biological Assay Biological Models Cell Proliferation Cells Circadian Dysregulation Circadian Rhythms Circadian gene expression Clinical Clinical Data Code Colorectal Cancer Colorectal Neoplasms Complex Computer Analysis Coupled DNA Damage Data Death Rate Development Diagnostic Neoplasm Staging Diet Dietary Factors Down-Regulation Eating Environmental Risk Factor Enzymes Epithelial Cells Genes Genetic Genome Genome Stability Genomic Instability Goals High Fat Diet Hormonal Human Incidence Intestinal Polyps Intestines Link Loss of Heterozygosity Malignant Neoplasms Maps Measures Mediating Metabolic Metabolic Pathway Metabolism Modeling Molecular Mus Mutation Oncogenic Organoids Pacemakers Pathogenesis Pathway interactions Patients Periodicity Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Polyps Prevention strategy Proliferating Reporting Research Risk Factors Role Sampling Signal Transduction Sleep Wake Cycle Stress Surveys Survival Rate System TP53 gene Testing The Cancer Genome Atlas Time-restricted feeding Tumor Suppressor Proteins United States WNT Signaling Pathway biobank c-myc Genes cancer diagnosis cancer prevention cancer type cell growth regulation circadian circadian pacemaker circadian regulation colon cancer patients colorectal cancer prevention colorectal cancer treatment dietary dietary control driver mutation early onset early onset colorectal cancer exome sequencing experimental study feeding human data insight interdisciplinary approach intestinal epithelium knock-down lifestyle factors metaplastic cell transformation mouse model novel nutrition older patient pharmacologic reconstitution response stable isotope stemness targeted treatment therapy development transcription factor transcriptome tumorigenesis young adult

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项目摘要

PROJECT SUMMARY/ ABSTRACT Colorectal cancer (CRC) is the third most diagnosed cancer in the United States. Though CRC cases in adults (55 and older) have decreased, the incidence of CRC in young adults, ages 15-40, is on an alarming rise. It is estimated that by the year 2030, a staggering 11-12% increase in early-onset (EO) cancers will be observed. Adult cases of CRC typically harbor driver mutations in Apc, a tumor suppressor that regulates Wnt signaling, in addition to second hits in Kras, Braf, p53 and Smad4. Apc mutations are also found in early-onset CRC (EO- CRC), but a decrease in the typical second hit driver pathways has been reported. Therefore, there is an urgent need to better define the root cause of EO-CRC. Moreover, clinical evidence suggests that diet is likely a root underlying cause of the increased incidence in sporadic cases of EO-CRC. Interestingly, dietary challenge and timing of food intake directly impinge on the circadian clock, which is our internal pacemaker that governs sleep/wake cycles, feeding, hormonal and other cyclic rhythms. This suggests that disruption of the circadian clock could be a major risk factor for EO cancers. In further support of this idea, clinical data indicates that clock genes are broadly downregulated in human colorectal tumors, suggesting that suppression of the clock could be important for transformation in the intestinal epithelium. To directly address the potential links between the clock and CRC, we have developed a novel genetic mouse model to define how disruption of the circadian clock drives CRC pathogenesis. Our preliminary data demonstrates that disruption of the clock in the intestinal epithelium drives a statistically significant increase in polyp formation. Using our mouse model system, organoid cultures reveal that clock disruption accelerates transformation in the intestinal epithelium. Based on these findings, we hypothesize that clock disruption impinges on intestinal transformation and rewires cellular metabolism to sustain the heightened demand of hyperproliferative cells. Aim 1 will define how the clock machinery regulates genome instability and transformation in the intestine. Aim 2 will determine the role of the circadian clock in governing metabolism of intestinal epithelial cells in both mouse and human organoid systems, established from EO-CRC patient samples. Aim 3 will delineate how dietary paradigms that disrupt the circadian clock accelerate intestinal transformation. The broader impact of our findings will outline new prevention strategies for eradicating EO-CRC and other cancers that potentially relate to disruption of the circadian clock. Additionally, our long-term goal is to achieve targeted pharmacological approaches to regulate the circadian clock and therefore minimize behavioral and lifestyle factors that potentially impinge on tumorigenesis.

项目摘要/摘要结直肠癌（CRC）是美国诊断出的第三大癌症。虽然成人的CRC病例（55岁及以上）有所下降，年轻人15-40岁的CRC的发生率令人震惊。这是据估计，到2030年，将观察到早发（EO）癌的惊人增长11-12％。 CRC的成年病例通常在APC中携带驱动器突变，APC是一种调节Wnt信号的肿瘤抑制器在KRAS，BRAF，P53和SMAD4中获得第二次命中。在早发CRC中也发现了APC突变（EO- CRC），但据报道典型的第二次命中驾驶途径的减少。因此，有一个紧急的需要更好地定义EO-CRC的根本原因。此外，临床证据表明饮食可能是根源 EO-CRC零星病例发病率增加的根本原因。有趣的是，饮食挑战和食物摄入的时间直接影响昼夜节律，这是我们的内部起搏器睡眠/唤醒周期，喂养，荷尔蒙和其他环状节奏。这表明昼夜节律的破坏时钟可能是EO癌症的主要危险因素。为了进一步支持这个想法，临床数据表明时钟基因在人类结直肠肿瘤中广泛下调，表明抑制时钟可能是对于肠上皮的转化很重要。直接解决时钟之间的潜在链接和CRC，我们开发了一种新型的遗传小鼠模型，以定义昼夜节律驱动器的破坏 CRC发病机理。我们的初步数据表明，肠上皮中时钟的破坏驱动息肉形成的统计学显着增加。使用我们的鼠标模型系统，器官培养物揭示时钟破坏会加速肠上皮的转化。基于这些发现，我们假设时钟的破坏会影响肠道转化并重新布置细胞代谢以维持高增殖细胞的需求增强。 AIM 1将定义时钟机械如何调节基因组肠中的不稳定性和转变。 AIM 2将确定昼夜节律在管理中的作用由EO-CRC建立的小鼠和人体器官系统中肠上皮细胞的代谢病人样本。 AIM 3将描述饮食范式如何破坏昼夜节律的肠道肠道转型。我们发现的更广泛的影响将概述消除EO-CRC的新预防策略以及其他可能与昼夜节律破坏有关的癌症。此外，我们的长期目标是实现有针对性的药理方法来调节昼夜节律，从而最大程度地减少行为以及可能影响肿瘤发生的生活方式因素。