exRNA in colorectal carcinoma: biogenesis and function

结直肠癌中的 exRNA：生物发生和功能

基本信息

批准号：
10544788
负责人：
Alissa M Weaver
金额：
$ 174.5万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-22 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10544788
关键词：
Address Affect Area Behavior Binding Biogenesis Biological Biological Models Biology Cell Communication Cell membrane Cell model Cell physiology Cell secretion Cells Cetuximab Communication Development Endoplasmic Reticulum Endosomes Epidermal Growth Factor Receptor Epigenetic Process Funding Gene Expression Goals Health Human Immune Intervention Intestines KRAS2 gene Large Intestine Carcinoma Ligands Lipids Malignant Epithelial Cell Malignant Neoplasms Mediating Methods MicroRNAs Modification Molecular Neoplasm Metastasis Nucleic Acids Organelles Organoids Patients Phenotype Post-Translational Protein Processing Proteins RNA RNA-Binding Proteins Repression Resistance Resource Sharing Role Signal Transduction Signaling Protein Sorting System Testing Tissues Transfer RNA United States Up-Regulation WNT Signaling Pathway Work cancer initiation cell type colonic crypt exosome extracellular extracellular vesicles inhibitor intercellular communication microvesicles novel particle programs stem cell niche synergism three dimensional cell culture trafficking tumor microenvironment tumor progression tumorigenesis

项目摘要

Summary – Overall Component Cellular communication between diverse cells is now recognized to heavily influence both cancer initiation and progression. Recently, several new forms of intercellular communication have been recognized, including exchange of proteins and RNAs via extracellular vesicles (EVs) and other carriers. Extracellular RNA (ExRNA) is particularly interesting, as it has the potential to influence gene expression and potentially epigenetic states. MicroRNAs (miRNAs) in particular have been shown to be transferred from one cell type to another to influence gene expression; however, it is clear that many kinds of exRNAs are selectively secreted from cells. What is less clear is how those exRNAs (including miRNAs) are packaged into EVs and other carriers. In addition, the overall impact of these exRNAs on cells and tissues is not yet understood. In this program, we propose to elucidate the “rules of the game” for extracellular RNA communication, using colorectal carcinoma (CRC) as a model system. Our Program will be highly synergistic, because each Project focuses on a different aspect of this problem. Thus, Project 1 will determine how subcellular contacts between organelles drive RNA and RNA-binding protein (RBP) transfer to EVs in CRC. Project 2 will identify RNA modifications and sequences that drive molecular selection of RNAs for transfer into EVs in CRC. Project 3 will identify how EVs and exomeres mediate EGFR-Wnt crosstalk in CRC. All Projects use common experimental systems, including CRC isogenic cell models, and have common biological focus (e.g. how miR-100 and miR-125b are trafficked and influence recipient cell function in CRC). Integration, synergy, and progress of the Projects will be highly enhanced by the proposed Administrative and Shared Resource Cores. Together this Program will make a major impact in the areas of CRC, tumor microenvironment, exRNA, EVs, and RNA biology.

摘要 – 总体组成部分现在人们认识到不同细胞之间的细胞通讯会严重影响癌症的发生和发展最近，人们认识到了几种新的细胞间通讯形式，包括通过细胞外囊泡 (EV) 和其他细胞外 RNA (ExRNA) 交换蛋白质和 RNA。特别有趣，因为它有可能影响基因表达和潜在的表观遗传状态。特别是 MicroRNA (miRNA) 已被证明可以从一种细胞类型转移到另一种细胞类型影响基因表达；然而，很明显许多种类的 exRNA 是从细胞中选择性分泌的。不太清楚的是这些 exRNA（包括 miRNA）如何被包装到 EV 和其他载体中。此外，在这个项目中，我们还不清楚这些 exRNA 对细胞和组织的总体影响。提议利用结直肠癌阐明细胞外 RNA 通讯的“游戏规则” （CRC）作为一个模型系统，我们的计划将具有高度的协同性，因为每个项目都侧重于不同的领域。因此，项目 1 将确定细胞器之间的亚细胞接触如何驱动 RNA。项目 2 中的 RNA 结合蛋白 (RBP) 转移至 EV 将识别 RNA 修饰和项目 3 中驱动 RNA 分子选择以转移至 EV 的序列将确定 EV 如何进行。和外泌体介导 CRC 中的 EGFR-Wnt 串扰所有项目都使用常见的实验系统，包括 CRC 同基因细胞模型，并且具有共同的生物学焦点（例如 miR-100 和 miR-125b 如何贩运并影响 CRC 中受体细胞的功能）。通过拟议的管理和共享资源核心，该计划将共同增强。在 CRC、肿瘤微环境、exRNA、EV 和 RNA 生物学领域产生重大影响。