A Chemopreventive Strategy Based on Edible MicroRNAs Produced in Plants

基于植物中产生的可食用 MicroRNA 的化学预防策略

• 批准号: 8772137
• 负责人: VICKI VANCE
• 金额: $ 7.33万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772137
• 关键词: Achievement; Address; Affect; American Cancer Society; Animal Model; Arabidopsis; Basic Science; Biogenesis; Biological Assay; Biological Models; Biological Process; Biology; Biomedical Engineering; Cancer Etiology; Canned Foods; Cell Culture System; Cell Proliferation; Cessation of life; Characteristics; Chemopreventive Agent; Colon; Colon Carcinoma; Colorectal Cancer; Custom; Development; Devices; Diagnosis; Diet; Disease; Eating; Edible Plants; Effectiveness; Engineering; Feasibility Studies; Gastrointestinal tract structure; Gene Targeting; Genetic Engineering; Genetic Models; Genetically Modified Plants; Human; Human Genome; Ingestion; Laboratories; Legal patent; Malignant Neoplasms; Mammals; Metabolism; Methods; Methylation; MicroRNAs; Mouse-ear Cress; Mus; Nutraceutical; Operative Surgical Procedures; Oral Administration; Outcome; Pathway interactions; Patients; Pharmacologic Substance; Pilot Projects; Plant RNA; Plants; Positioning Attribute; Preventive; Production; Public Health; RNA; Recurrence; Regimen; Replacement Therapy; Research; Research Design; Research Personnel; Role; Small Intestines; Small RNA; Source; Staging; System; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Transgenic Plants; Translations; Treatment Protocols; Tumor Burden; Tumor Suppressor Proteins; Work; anticancer research; base; cancer diagnosis; cancer therapy; carcinogenesis; clinical application; cost effective; effective therapy; experience; feeding; human disease; large scale production; mouse model; novel; plant genetics; prevent; public health relevance; research study; restoration; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the third most commonly diagnosed cancer and a leading cause of cancer deaths in the US. The primary treatment is surgery, which can be curative especially in early stages of CRC. However, recurrence of the disease is a major problem, and is often fatal. Thus, development of new chemopreventive strategies for CRC remains a high priority. MicroRNAs (miRNAs) are an emerging class of therapeutic agents with significant translational potential for the treatment of cancer. Many different forms of cancer, including CRC, are associated with loss or reduced accumulation of one or more miRNAs that function as tumor suppressors. In animal models, restoration of the missing tumor suppressor miRNA prevents the initiation, progression and/or spread of the disease, suggesting a promising therapeutic role for these small RNAs. However, the current absence of an efficient method for systemic delivery of therapeutic miRNAs is a critical barrier to their use in cancer therapies. The proposed pilot project will test a novel chemopreventive strategy for miRNA replacement therapy based on ingestion of plants that have been bioengineered to produce therapeutic miRNAs. The work builds on our promising preliminary results showing that oral administration of plant RNA spiked with a cocktail of three tumor-suppressor miRNAs (miR-34a, -143, and -145), synthesized with the 3'-methylation characteristic of plant miRNAs, has significant chemopreventive activity in the ApcMin/+ mouse model of CRC. In Aim 1 of the proposed feasibility study, we will determine the combination of the three miRNAs that is most effective in suppressing tumorigenesis when delivered orally to ApcMin/+ mice. The research design is to feed plant RNA spiked with various combinations of synthesized tumor suppressor miRNAs to the mice either before or after tumors have developed (preventive and therapeutic regimens, respectively) and determine the impact of the treatment by assaying tumor burden, level of administered therapeutic miRNAs and expression of select miRNA target genes in treatment versus control tissues. Although the commercially synthesized miRNAs used in our pilot study and in Aim 1 allow rapid testing of specific miRNA replacement strategies, they are prohibitively expensive for translation to humans. Therefore, in Aim 2, we will establish transgenic plant line(s) producing high levels of the most effective combination(s) of tumor suppressor miRNAs as determined in Aim 1, and assay their impact when fed to ApcMin/+ mice via a custom diet. The concept of producing therapeutic miRNAs in edible plants has significant potential in basic, translational and clinical applications and provides a cost-effective alternative to currently available synthetic RNA production methods. Our group is uniquely positioned to undertake this project based on complementary expertise of the investigators. Dr. Vance is a pioneer in small RNA biology in plants and is primary co-inventor on patented technology for the use of genetically engineered miRNAs produced in plants, and Dr. Pena has many years of experience and a strong record of achievement in CRC research using mouse model systems.

简介(申请人提供)：结直肠癌(CRC)是美国第三种最常见的癌症，也是导致癌症死亡的主要原因。手术是主要的治疗方法，尤其是在早期结直肠癌中，手术是可以治愈的。然而，该病的复发是一个主要问题，而且往往是致命的。因此，为结直肠癌制定新的化学预防战略仍然是一个高度优先的问题。MicroRNAs(MiRNAs)是一类新兴的治疗药物，在癌症治疗中具有巨大的翻译潜力。许多不同形式的癌症，包括结直肠癌，都与一个或多个发挥肿瘤抑制作用的miRNAs的丢失或减少积累有关。在动物模型中，缺失的肿瘤抑制因子miRNA的修复可以防止疾病的发生、发展和/或扩散，这表明这些小RNA具有很好的治疗作用。然而，目前缺乏有效的系统递送治疗性miRNAs的方法是阻碍 它们在癌症治疗中的应用。拟议的试点项目将测试一种新的miRNA替代疗法的化学预防策略，该策略基于摄取已被生物工程改造为生产治疗性miRNA的植物。这项工作建立在我们有希望的初步结果的基础上，该结果表明，口服添加了三种抑癌基因miRNAs(miR-34a、-143和-145)的鸡尾酒的植物RNA，利用植物miRNAs的3‘-甲基化特性合成的，在ApcMin/+小鼠模型中具有显著的化学预防活性。在拟议的可行性研究的目标1中，我们将确定口服给ApcMin/+小鼠时在抑制肿瘤形成方面最有效的三种miRNAs的组合。这项研究的设计是在肿瘤形成之前或之后(分别为预防和治疗方案)将添加了各种合成肿瘤抑制因子miRNAs组合的植物RNA喂给小鼠，并通过分析肿瘤负担、给予治疗性miRNAs的水平以及治疗与对照组织中选定的miRNA靶基因的表达来确定治疗的影响。尽管在我们的初步研究和目标1中使用的商业合成的miRNAs允许快速测试特定的miRNA替换策略，但它们对于翻译到人类身上来说是昂贵的。因此，在目标2中，我们将建立高水平的转基因植物系(S)，该株系产生目标1中所确定的肿瘤抑制基因最有效的组合(S)，并通过定制饲料喂养ApcMin/+小鼠来分析它们的影响。在可食用植物中生产治疗性miRNAs的概念在基础、翻译和临床应用方面具有巨大的潜力，并为目前可用的合成RNA生产方法提供了一种经济有效的替代方法。我们的团队处于独特的地位，可以基于调查人员的互补专业知识来开展这一项目。万斯博士是植物小RNA生物学的先驱，也是使用植物中产生的基因工程miRNAs的专利技术的主要共同发明人，佩纳博士在使用小鼠模型系统进行CRC研究方面拥有多年的经验和出色的成就。