Role of M3 muscarinic receptors in bile acid-induced colon cancer

M3毒蕈碱受体在胆汁酸诱导的结肠癌中的作用

基本信息

批准号：
7888241
负责人：
JEAN-PIERRE RAUFMAN
金额：
$ 31.13万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7888241
关键词：
Aberrant crypt foci Ablation Address Adenocarcinoma Adenomatous Polyposis Coli Agonist Animal Model Animals Area Attenuated Azoxymethane Bile Acids Binding Bromodeoxyuridine Cancer Biology Cancer Etiology Cancer Model Cause of Death Cell Proliferation Cells Cessation of life Cholinergic Agonists Colon Colon Carcinoma Colonic Neoplasms DTR gene Data Development Diagnosis Disease Epidemiology Epidermal Growth Factor Receptor Epithelial Cell Proliferation Epithelial Cells Extracellular Signal Regulated Kinases Figs - dietary Gene Mutation Genes Genetic Genetic Transcription Goals Health Human Infusion procedures Intestinal Neoplasms Intestines Investigation Knowledge Ligands Link Matrilysin Mediating Methods Mitogen-Activated Protein Kinases Modeling Molecular Morbidity - disease rate Mus Muscarinic Acetylcholine Receptor Muscarinic M3 Receptor Neoplasms Operative Surgical Procedures Outcome Persons Population Receptor Activation Receptor Signaling Regulation Research Research Personnel Risk Role Scopolamine Signal Transduction Small Intestinal Adenoma Taurodeoxycholic Acid Testing Time Transactivation Transcriptional Activation Treatment Efficacy United States Woman Work adenoma attenuation base cancer cell cancer risk carcinogenesis colon cancer cell line colon carcinogenesis darifenacin experience gastrointestinal high risk in vivo innovation men mortality neoplastic new therapeutic target novel novel strategies prevent public health relevance receptor expression research study tumor

项目摘要

DESCRIPTION (provided by applicant): For men and women in the United States, colon cancer is the third most common cause of cancer death and the leading gastrointestinal cause of death. Epidemiological and animal studies associate colon cancer risk with alterations in the spectrum and concentration of fecal bile acids. The present line of investigation was initiated by our unanticipated observation that bile acids interact with muscarinic receptors. M3 muscarinic receptors (M3R), which are over-expressed in most colon cancers, are key players in colon cancer cell proliferation. Our data indicate that bile acids interact functionally with M3R expressed on human colon cancer cell lines thereby activating matrix metalloproteinase (MMP)-7, releasing HB-EGF, and inducing transactivation of epidermal growth factor receptors (EGFR). Post-receptor signaling via ERK stimulates human colon cancer cell proliferation. Collectively, these observations identify M3R as a novel therapeutic target to prevent and/or treat colon cancer. The central hypothesis of this revised R01 application is that M3R expression and activation in vivo mediates bile acid promotion of intestinal neoplasia. In mice treated with a procarcinogen [azoxymethane (AOM)] and mice with an apc gene mutation (ApcMin/+ mice), our preliminary findings show that M3R-deficiency reduces intestinal tumor number. Primary goals of the revised research plan are to use these unique murine colon cancer models to establish the importance of M3R expression for development of colon neoplasia, to identify molecular mechanisms whereby bile acid-induced activation of M3R promotes carcinogenesis, and to establish that pharmacologic inhibition of M3R activation mimics m3r gene ablation thereby attenuating intestinal neoplasia. To test our central hypothesis and address these goals we propose three focused Specific Aims: Aim 1. Establish the critical role of M3R expression for murine intestinal neoplasia. Aim 2. Establish that bile acid-induced M3R activation promotes intestinal neoplasia by ERK- mediated gene transcription. Aim 3. Establish that pharmacologic inhibition of M3R mimics the effects of m3r gene ablation and reduces intestinal neoplasia. This revised application includes strong preliminary data supporting our central hypothesis, a focused approach to defining the mechanisms whereby M3R and bile acids promote colon carcinogenesis, unique animal models, innovative methods, and an outstanding group of highly experienced co-investigators and consultants. Based on our provocative preliminary data supporting the key role of M3R in colon tumor formation, it is timely and important to determine whether blocking M3R activation with anti-muscarinic receptor agents mimics the reduction in tumor number observed in M3R-deficient mice. Outcomes will establish the critical role of M3R and advance human health by spurring development of pharmacologic strategies to prevent and treat colon neoplasia by attenuating muscarinic receptor activation. At the same time, fundamental knowledge gained regarding the role of muscarinic receptors in mediating bile acid actions and neoplasia will advance the general area of cancer biology. PUBLIC HEALTH RELEVANCE: For men and women colon cancer is a leading cause of morbidity and mortality; in the US, approximately 150,000 people are diagnosed and 50,000 die from colon cancer each year. Efficacy of treatment for advanced colon cancer is limited and new approaches are needed. It is anticipated that the proposed investigation on the critical role of M3 muscarinic receptors in intestinal neoplasia will reveal a novel, low-risk strategy to prevent colon cancer in high-risk populations (e.g. those with familial adenomatous polyposis syndrome) and to treat this important, frequently deadly disease in those who cannot be cured with surgery.

描述（由申请人提供）：对于美国男性和女性来说，结肠癌是癌症死亡的第三大常见原因，也是导致胃肠道死亡的主要原因。流行病学和动物研究将结肠癌风险与粪便胆汁酸谱和浓度的变化联系起来。目前的研究路线是由我们意想不到的观察结果引发的，即胆汁酸与毒蕈碱受体相互作用。 M3 毒蕈碱受体 (M3R) 在大多数结肠癌中过度表达，是结肠癌细胞增殖的关键因素。我们的数据表明，胆汁酸与人结肠癌细胞系上表达的 M3R 发生功能性相互作用，从而激活基质金属蛋白酶 (MMP)-7，释放 HB-EGF，并诱导表皮生长因子受体 (EGFR) 的反式激活。通过 ERK 的受体后信号传导刺激人结肠癌细胞增殖。总的来说，这些观察结果将 M3R 确定为预防和/或治疗结肠癌的新治疗靶点。修订后的 R01 应用的中心假设是 M3R 体内表达和激活介导胆汁酸促进肠道肿瘤形成。在用原致癌物[氧化偶氮甲烷 (AOM)] 治疗的小鼠和具有 apc 基因突变的小鼠（ApcMin/+ 小鼠）中，我们的初步研究结果表明 M3R 缺陷减少了肠道肿瘤数量。修订后的研究计划的主要目标是利用这些独特的小鼠结肠癌模型来确定 M3R 表达对结肠肿瘤发展的重要性，确定胆汁酸诱导的 M3R 激活促进致癌的分子机制，并确定药物抑制M3R 激活模拟 m3r 基因消融，从而减轻肠道肿瘤。为了检验我们的中心假设并实现这些目标，我们提出了三个重点具体目标：目标 1. 确定 M3R 表达对小鼠肠道肿瘤的关键作用。目标 2. 确定胆汁酸诱导的 M3R 激活通过 ERK 介导的基因转录促进肠肿瘤形成。目标 3. 确定 M3R 的药理学抑制模拟 m3r 基因消融的效果并减少肠道肿瘤。该修订后的申请包括支持我们中心假设的强有力的初步数据、定义 M3R 和胆汁酸促进结肠癌发生机制的重点方法、独特的动物模型、创新方法以及经验丰富的合作研究人员和顾问组成的杰出团队。基于我们支持 M3R 在结肠肿瘤形成中关键作用的令人兴奋的初步数据，确定用抗毒蕈碱受体药物阻断 M3R 激活是否模拟在 M3R 缺陷小鼠中观察到的肿瘤数量减少是及时且重要的。结果将确定 M3R 的关键作用，并通过刺激药理学策略的开发，通过减弱毒蕈碱受体的激活来预防和治疗结肠肿瘤，从而促进人类健康。与此同时，关于毒蕈碱受体在介导胆汁酸作用和肿瘤形成中的作用所获得的基础知识将推动癌症生物学的一般领域的发展。公共卫生相关性：对于男性和女性来说，结肠癌是发病和死亡的主要原因；在美国，每年约有 150,000 人被诊断出患有结肠癌，50,000 人死于结肠癌。晚期结肠癌的治疗效果有限，需要新的方法。预计对 M3 毒蕈碱受体在肠道肿瘤中的关键作用进行的研究将揭示一种新颖的低风险策略，以预防高风险人群（例如患有家族性腺瘤性息肉病综合征的人群）的结肠癌并治疗这一重要疾病。，对于那些无法通过手术治愈的人来说，通常是致命的疾病。