MicroRNA-1291 in Regulation of Xenobiotic Disposition and Cell Differentiation

MicroRNA-1291 调节异生素处置和细胞分化

基本信息

批准号：
8848050
负责人：
Aiming Yu
金额：
$ 33.15万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
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：
2014-05-12 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8848050
关键词：
ABCC1 gene ABCG2 gene AGR2 gene AKT2 gene ATP-Binding Cassette Transporters Adverse effects Affect Animal Model Animals Antineoplastic Agents Arts Biochemical Biological Models Blood Chemical Analysis Boxing Breast Cancer Cell Breast Cancer cell line CYP3A4 gene Cell Cycle Arrest Cell Differentiation process Cell Proliferation Cell physiology Cells Clinical Code Cytochrome P450 Development Doxorubicin Drug Controls Drug Regulations Effectiveness Enzymes Foundations Gene Expression Gene Targeting Genes Goals Health Histology Homeostasis Human Human Cell Line Immune response In Vitro Laboratories Life Malignant Neoplasms Malignant neoplasm of pancreas MicroRNAs Modeling Molecular Multi-Drug Resistance P-Glycoprotein Pancreatic Ductal Adenocarcinoma Patients Pharmaceutical Preparations Pharmacotherapy Process Prostaglandins Proteins Proteomics Quality Control Regulation Renal function Research Role Safety Sampling Techniques Testing Therapeutic Tissues Tumor Suppressor Proteins Tumor Tissue Untranslated RNA Work Xenobiotics Xenograft procedure base cancer cell cancer cell differentiation cancer therapy cell growth regulation clinically relevant cytokine differential expression drug development gemcitabine improved in vivo innovation insight liver function loss of function metabolomics mouse model neoplastic novel poly(lactide)rac-PK beta restoration translational study tumor tumor progression tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Understanding the molecular mechanisms in the control of xenobiotic disposition is critical for rational drug development and therapy. Although some mechanisms are known, much remains undefined. MicroRNAs (miRNAs) are a large group of recently identified, short, noncoding RNAs that govern target gene expression in cells. The PI's laboratory has demonstrated that several miRNAs (e.g., miR-27b, -328 and -519c) control posttranscriptional regulation of cytochrome P450 enzymes (e.g., CYP3A4) and ABC transporters (e.g., ABCG2), and consequently affect drug disposition. Furthermore, there is increasing evidence that some miRNAs are differentially expressed in human tumor and non-tumor tissues. Indeed, several aberrantly expressed miRNAs (e.g., miR-34a) have been identified as master regulators of cancer cellular processes. Very recently, the PI's group has revealed that a previously uncharacterized miRNA miR-1291 modulates intracellular doxorubicin accumulation and chemosensitivity via direct targeting of ABCC1. In addition, miR-1291 is significantly downregulated in human pancreatic ductal adenocarcinoma (PDAC) as well as pancreatic and breast cancer cell lines. Restoration of miR-1291 function inhibits tumorigenesis in vivo, which is associated with an induction of cell cycle arrest in vitro. Therefore, studies ar proposed to test the hypothesis that miR-1291 controls multiple cellular processes through the regulation of target genes, and miR-1291 may be utilized to treat cancers or improve the efficacy of anticancer drugs (e.g., doxorubicin). Aim 1 is to delineate the mechanistic functions of miR-1291 in the regulation of drug disposition and endobiotics homeostasis. Aim 2 is to define the roles and molecular mechanisms of miR-1291 in the control of cancer cell proliferation, invasion, and tumor progression processes. Aim 3 is to establish the effectiveness and safety profiles of miR-1291 therapeutics in clinically relevant animal models. The feasibility of the proposed research is supported by exciting preliminary findings obtained from patient samples as well as animal and human cell line models. Results are anticipated to establish the mechanistic roles of miR-1291 in the regulation of drug disposition and cell differentiation processes, and lay the basic foundation for the development of miR-1291-based therapy.

描述（由申请人提供）：了解控制异生素处置的分子机制对于合理的药物开发和治疗至关重要。尽管一些机制是已知的，但还有很多机制尚未定义。 MicroRNA (miRNA) 是一大类最近发现的短非编码 RNA，它们控制细胞中的靶基因表达。 PI 实验室已证明，多种 miRNA（例如 miR-27b、-328 和 -519c）控制细胞色素 P450 酶（例如 CYP3A4）和 ABC 转运蛋白（例如 ABCG2）的转录后调节，从而影响药物处置。此外，越来越多的证据表明，一些 miRNA 在人类肿瘤和非肿瘤组织中存在差异表达。事实上，一些异常表达的 miRNA（例如 miR-34a）已被确定为癌症细胞过程的主要调节因子。最近，PI 团队揭示了一种先前未表征的 miRNA miR-1291 通过直接靶向 ABCC1 来调节细胞内阿霉素的积累和化疗敏感性。此外，miR-1291 在人胰腺导管腺癌 (PDAC) 以及胰腺癌细胞系和乳腺癌细胞系中显着下调。 miR-1291 功能的恢复可抑制体内肿瘤发生，这与体外诱导细胞周期停滞有关。因此，提出研究来检验miR-1291通过靶基因的调节来控制多个细胞过程的假设，并且miR-1291可用于治疗癌症或提高抗癌药物（例如阿霉素）的疗效。目标 1 是描述 miR-1291 在调节药物分布和内生素稳态中的机制功能。目标 2 是明确 miR-1291 在控制癌细胞增殖、侵袭和肿瘤进展过程中的作用和分子机制。目标 3 是在临床相关动物模型中建立 miR-1291 疗法的有效性和安全性。从患者样本以及动物和人类细胞系模型中获得的令人兴奋的初步结果支持了拟议研究的可行性。预计结果将确定 miR-1291 在调节药物分布和细胞分化过程中的机制作用，并为基于 miR-1291 的疗法的开发奠定基础。