MicroRNA-1291 in Regulation of Xenobiotic Disposition and Cell Differentiation

描述（由申请人提供）：了解控制外源性处置的分子机制对于合理的药物开发和治疗至关重要。虽然一些机制是已知的，但许多机制仍未确定。MicroRNAs （miRNAs）是最近发现的一大类控制细胞中靶基因表达的短非编码rna。PI的实验室已经证明，几种mirna（例如，miR-27b， -328和-519c）控制细胞色素P450酶（例如，CYP3A4）和ABC转运体（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在人类肿瘤组织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）已被确定为癌细胞过程的主要调节因子。最近，PI的研究小组发现，一种以前未被表征的miRNA miR-1291通过直接靶向ABCC1调节细胞内阿霉素的积累和化学敏感性。此外，miR-1291在人胰导管腺癌（PDAC）以及胰腺癌和乳腺癌细胞系中显著下调。miR-1291功能的恢复在体内抑制肿瘤发生，这与体外诱导细胞周期阻滞有关。因此，我们提出研究来验证miR-1291通过调控靶基因控制多个细胞过程的假设，miR-1291可能被用于治疗癌症或提高抗癌药物（如阿霉素）的疗效。目的1是描述miR-1291在药物处置和内源性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发现支持了拟议研究的可行性。研究结果有望确立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的治疗的发展奠定基础。

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.