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

基本信息

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
项目类别：
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

项目摘要

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.

描述（由申请人提供）：大肠癌（CRC）是美国第三大常见的癌症，是美国癌症死亡的主要原因。主要治疗方法是手术，尤其是在CRC的早期阶段进行治疗。但是，这种疾病的复发是一个主要问题，通常是致命的。因此，针对CRC的新化学预防策略的发展仍然是一个很高的优先事项。 microRNA（miRNA）是一类新兴的治疗剂，具有巨大的转化潜力来治疗癌症。包括CRC在内的许多不同形式的癌症与损失或减少充当肿瘤抑制子的miRNA的积累相关。在动物模型中，恢复缺失的肿瘤抑制剂miRNA可防止疾病的启动，进展和/或传播，这表明这些小RNA具有有前途的治疗作用。但是，目前缺乏有效的治疗miRNA的系统性输送方法是对的关键障碍它们用于癌症疗法。拟议的试点项目将基于对生物工程生产治疗性miRNA的植物的摄入，测试一种新型的miRNA替代化学预防策略。这项工作以我们有希望的初步结果为基础，表明，口服植物RNA用三种肿瘤 - 抑制剂miRNA（miR-34a，-143和-145）的鸡尾酒升高，并与植物miRNA的3'-甲基化特征合成，具有显着的化学化学作用。在拟议的可行性研究的目标1中，我们将确定三种miRNA的组合，这些miRNA在口服递送至apcmin/+小鼠时最有效地抑制肿瘤发生。研究设计是为了在肿瘤发生之前或之后喂养合成肿瘤抑制miRNA的各种组合的植物RNA（分别分别（分别是预防和治疗方案）），并通过分析肿瘤负担，疗法miRNAS的水平和选择miRNA靶基因在治疗中的肿瘤负担来确定治疗的影响。尽管我们的试点研究和AIM 1中使用的商业合成的miRNA允许快速测试特定的miRNA替代策略，但它们对于转化为人类而言却非常昂贵。因此，在AIM 2中，我们将建立转基因植物线，以产生AIM 1中确定的最有效组合的肿瘤抑制miRNA，并通过自定义饮食对APCMIN/+小鼠进行分析。在可食用植物中产生治疗性miRNA的概念在基本，转化和临床应用中具有巨大的潜力，并为当前可用的合成RNA生产方法提供了一种具有成本效益的替代方法。我们的小组在基于调查人员的互补专业知识中独特地定位了该项目。 Vance博士是植物中小RNA生物学的先驱，并且是使用专利技术的主要共同发明，用于使用植物中生产的基因工程的miRNA，Pena博士拥有多年的经验，并且使用了小鼠模型系统的CRC研究中有很多经验。