MicroRNA-1291 in Regulation of Xenobiotic Disposition and Cell Differentiation

MicroRNA-1291 调节异生素处置和细胞分化

• 批准号: 9232088
• 负责人: Aiming Yu
• 金额: $ 31.03万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 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/9232088
• 关键词: ABCC1 gene; ABCG2 gene; AGR2 gene; AKT2 gene; ATP-Binding Cassette Transporters; Adverse effects; Affect; Animal Model; Animals; Antineoplastic Agents; Biochemical; Biological Models; Blood Chemical Analysis; Breast Cancer Cell; Breast Cancer cell line; CYP3A4 gene; Cancer Control; Cations; 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; 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; Untranslated RNA; 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; in vivo Model; innovation; insight; liver function; loss of function; metabolomics; mouse model; novel; poly(lactide); public health relevance; rac-PK beta; restoration; therapeutic miRNA; translational study; tumor; tumor progression; tumor xenograft; tumorigenesis

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）：了解控制异生物质处置的分子机制对于合理的药物开发和治疗至关重要。虽然有些机制是已知的，但仍有许多机制尚未确定。microRNAs（miRNAs）是近年来发现的一大类短的非编码RNA，在细胞中调控靶基因的表达。PI的实验室已经证明了几种miRNAs（例如，miR-27 b、-328和-519 c）控制细胞色素P450酶（例如，CYP 3A 4）和ABC转运蛋白（例如，ABCG 2），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差异表达。事实上，几种异常表达的miRNA（例如，miR-34 a）已被鉴定为癌症细胞过程的主要调节因子。最近，PI的研究小组揭示了一种以前未表征的miRNA miR-1291通过直接靶向ABCC 1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）以及胰腺癌和乳腺癌细胞系中显著下调。miR-1291功能的恢复抑制体内肿瘤发生，这与体外细胞周期停滞的诱导相关。因此，提出了研究来检验miR-1291通过调节靶基因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）。目的1：阐明miR-1291在药物处置和内稳态调节中的机制功能。目的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。目的3是在临床相关动物模型中建立miR-1291治疗剂的有效性和安全性特征。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发现支持了拟议研究的可行性。预计结果将确定miR-1291在调节药物处置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。