exRNA in colorectal carcinoma: biogenesis and function

结直肠癌中的 exRNA：生物发生和功能

• 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
• 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

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--总体组件 不同细胞之间的细胞通讯现在被认为在很大程度上影响癌症的启动和 进步。最近，已经认识到几种新的细胞间通信形式，包括 通过胞外小泡(EVS)和其他载体交换蛋白质和RNA。胞外RNA(ExRNA) 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。 尤其是microRNAs(MiRNAs)已经被证明从一种细胞类型转移到另一种细胞类型，从而 影响基因表达；然而，很明显，许多种类的exRNAs是选择性地从细胞中分泌出来的。 不太清楚的是，这些exRNAs(包括miRNAs)是如何包装成电动汽车和其他载体的。在……里面 此外，这些exRNA对细胞和组织的整体影响尚不清楚。在这个节目中，我们 以结直肠癌为例，提出阐明细胞外RNA通讯的“游戏规则” (CRC)作为示范制度。我们的计划将是高度协同的，因为每个项目侧重于不同的 这个问题的一个方面。因此，项目1将确定细胞器之间的亚细胞联系如何驱动RNA 和RNA结合蛋白(RBP)在结直肠癌中转移到EVS。项目2将确定RNA修改和 在CRC中驱动RNA分子选择以转移到EVS的序列。项目3将确定电动汽车如何 在结直肠癌中，外显子介导了EGFR-WNT串扰。所有项目都使用常见的实验系统，包括 CRC同源细胞模型，并具有共同的生物焦点(例如，miR-100和miR-125b是如何被贩卖的 并影响CRC中的受体细胞功能)。项目的整合性、协同性和进步性将非常高 因拟议的行政和共享资源核心而得到加强。这一计划将共同使 在结直肠癌、肿瘤微环境、外源RNA、EVS和RNA生物学等领域产生重大影响。