Circadian Clock Disruption and Colorectal Cancer

昼夜节律紊乱与结直肠癌

基本信息

批准号：
10061582
负责人：
Selma Masri
金额：
$ 35.91万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10061582
关键词：
APC gene ARNTL gene Address Area Biological Pacemakers Cancer Control Cancer Etiology Cell Cycle Cell Fate Control Cell Maintenance Cell Proliferation Cells Cessation of life Circadian Dysregulation Circadian Rhythms Clinical Colorectal Cancer Colorectal Neoplasms Critical Pathways Cues Development Disease Progression Early Diagnosis Endocrine Epigenetic Process Exhibits Future Gene Expression Genes Genetic Genetic Transcription Genetically Engineered Mouse Goals Growth Homeostasis Hour Human In Vitro Incidence Intestinal Cancer Intestines Jet Lag Syndrome Knowledge Light Link Maintenance Malignant Neoplasms Metabolism Modeling Molecular Mutation Neoplasm Metastasis Oncogenic Organoids Outcome Pathogenesis Pathology Pathway interactions Pharmacology Physiological Polyps Population Regulation Research Role Sex Differences Signal Pathway Signal Transduction Therapeutic Intervention Tissues Tumor stage United States WNT Signaling Pathway Work adenoma age related beta catenin cancer diagnosis cancer initiation chemotherapy circadian circadian pacemaker colorectal cancer treatment early screening gene repression in vivo insight intestinal adenoma molecular clock novel programs stem cells targeted treatment therapeutic target transcription factor tumor tumor initiation tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is the third leading cause of cancer-related deaths and the third most commonly diagnosed cancer in the United States. Despite the advantages of polyp screening for early detection, treatment options for advanced CRC rely on aggressive chemotherapy. Therefore, targeted therapy for the treatment of CRC is critically needed. Strikingly, clinical evidence has shown that compared to normal intestinal tissue, human colorectal tumors exhibit a down-regulation of gene expression of all components of the circadian clock molecular machinery. The circadian clock is the endogenous biological pacemaker which controls several physiological, endocrine and metabolic processes that operate to maintain organismal homeostasis within a strict 24- hour period. Several lines of evidence suggest that disruption of circadian rhythms results in cancer, yet the precise molecular mechanisms and detailed signaling pathways have yet to be elucidated. Moreover, the crosstalk between the circadian clock and proliferative pathways in the intestine is not fully elucidated, and more specifically, how this crosstalk is involved in CRC initiation and progression in vivo remains unresolved. To address this knowledge gap, we have generated a novel genetically engineered mouse model (GEMM) to elucidate the effects of circadian clock disruption on intestinal cell proliferation and CRC. We propose that genetic disruption of the molecular clock machinery aberrantly drives Wnt/b-Catenin signaling in the intestine. One goal of this proposal is to delineate the role of the circadian clock on Wnt- dependent proliferation pathways in the intestine, including pathways that govern cancer-initiating cell populations. A second goal of this proposal is to define the molecular mechanism of how the circadian clock impinges on Wnt/b-Catenin dependent transcriptional and epigenetic pathways. Our studies have important clinical implications in understanding how disruption of the biological pacemaker, on the molecular level, alters tumor initiation and disease progression to CRC. These findings provide novel insight into the potential for therapeutic targeting of the circadian clock for treatment of CRC, in addition to other tumors types dependent on activated Wnt signaling.

项目概要/摘要结直肠癌 (CRC) 是癌症相关死亡的第三大原因，美国第三大最常诊断的癌症。尽管有优势息肉筛查以实现早期发现，晚期结直肠癌的治疗选择依赖于积极的化疗。因此，针对CRC的治疗，靶向治疗是迫切需要。引人注目的是，临床证据表明，与正常人相比肠道组织、人类结直肠肿瘤表现出基因表达下调生物钟分子机械的所有组成部分。生物钟是内源性生物起搏器，控制多种生理、内分泌和代谢过程在严格的 24 小时内维持机体稳态小时期间。多项证据表明，昼夜节律被破坏导致癌症，但精确的分子机制和详细的信号传导途径尚未阐明。此外，生物钟之间的串扰肠道中的增殖途径尚未完全阐明，更具体地说，这种串扰如何参与体内 CRC 的发生和进展仍有待研究未解决。为了解决这一知识差距，我们产生了一种新颖的基因工程小鼠模型（GEMM）阐明生物钟破坏的影响对肠细胞增殖和结直肠癌的影响。我们建议，基因破坏分子钟机制异常驱动肠道中的 Wnt/b-Catenin 信号传导。该提案的一个目标是描述生物钟在 Wnt 上的作用肠道内的依赖性增殖途径，包括控制途径癌症起始细胞群。该提案的第二个目标是定义生物钟如何影响 Wnt/b-Catenin 依赖性的分子机制转录和表观遗传途径。我们的研究具有重要的临床意义了解生物起搏器如何在分子水平上受到破坏，改变肿瘤发生和疾病进展为 CRC。这些发现提供了新颖的深入了解生物钟治疗靶向的潜力 CRC 以及依赖于激活的 Wnt 信号传导的其他肿瘤类型。