In Vivo Regulated Release and Function of Extracellular Small RNAs

细胞外小 RNA 的体内调节释放和功能

• 批准号: 8713966
• 负责人: Robert Blelloch
• 金额: $ 146.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8713966
• 关键词: Animal Model; Area; Biochemistry; Biological Markers; Body Fluids; Caenorhabditis elegans; Destinations; Development; Diagnosis; Diagnostic; Disease; Fostering; Functional RNA; Goals; Health; Human; Image; Immune; Immune system; Knowledge; Lipids; Liver; MicroRNAs; Mission; Mus; Neoplasm Metastasis; Neurons; Prostate; Public Health; Research; Research Personnel; Role; Scientist; Signal Transduction; Small RNA; Source; System; Therapeutic Intervention; Tissues; Work; base; clinically relevant; extracellular; human disease; improved; in vivo; insight; lipid metabolism; member; relating to nervous system; tumor growth; tumor progression

DESCRIPTION (provided by applicant): There is a desperate need for new means to diagnose and treat most human diseases. Extracellular small RNAs provide great promise. In particular, recent findings provide strong evidence for their utility as biomarkers. Furthermore, very recent work shows functional roles for at least a subset of the extracellular small RNAs, which provides an opportunity for their manipulation in the treatment of disease. However, as the field is so recent with only anecdotal evidence in limited systems, there remains a fundamental gap in our knowledge of how wide spread the phenomenon of functional extracellular small RNAs really is and how can its potential be fully realized. This U19 Center's long-term goal is to uncover paradigms of extracellular small RNA function in health and disease and apply those paradigms to clinically relevant settings including biomarker discovery and therapeutic intervention. Members of the Center already have a significant track record in these areas. The objective here is to delve into the mechanism and role of small non-coding RNA secretion looking for unifying themes across tissues including the immune system, the liver, the prostate, and neural system and across species from C.elegans to mouse to human. The overarching hypothesis is that extracellular small RNAs represents a heterogeneous landscape that ranges from miRNA dumping to active signaling, and which can be differentiated based on the selectivity and form of their release into body fluids. The Center proposes to tackle this hypothesis by integrating the efforts of six principle investigators with expertise in differet types of small non-coding RNAs, in multiple model organisms, in the biochemistry of secretion and metabolism of lipid, and in imaging. The Center will consist of four projects and a scientific core dedicated to the isolation and characterization of lipid-associated and lipid-free forms of extracellular small RNAs. The aims will be to determine the source, the form, the destination, and the function of extracellular small RNAs in four distinct settings: immune stimulation, primary cancer progression, metastatic tumor growth, and olfactory neuron stimulation. Completion of these aims is expected to uncover common paradigms as well as distinct mechanisms reflecting the different drivers across these settings. This U19 Center proposal is highly significant as it will provide a vertical leap in our knowledge of what extracellular small RNAs represent and what their downstream functions are. This knowledge will enable improved insights into how to use extracellular small RNAs to follow disease and how to manipulate their levels in order to treat disease.

描述(申请人提供)：迫切需要新的方法来诊断和治疗大多数人类疾病。细胞外的小RNA提供了巨大的希望。特别是，最近的发现为它们作为生物标记物的效用提供了强有力的证据。此外，最近的工作显示了细胞外小RNA的至少一个子集的功能作用，这为它们在疾病治疗中的操纵提供了机会。然而，由于这一领域是最近才出现的，在有限的系统中只有传闻证据，对于功能性细胞外小RNA现象的广泛传播以及如何充分发挥其潜力，我们的认识仍然存在根本差距。该U19中心的长期目标是揭示健康和疾病中细胞外小RNA功能的范例，并将这些范例应用于临床相关环境，包括生物标记物的发现和治疗干预。该中心的成员在这些领域已经有了很好的记录。这里的目的是深入研究小的非编码RNA分泌的机制和作用，寻找跨组织的统一主题，包括免疫系统、肝脏、前列腺和神经系统，以及从线虫到小鼠再到人的跨物种。最重要的假设是，细胞外小RNA代表了一个从miRNA倾倒到主动信号传递的异质格局，并且可以根据它们释放到体液中的选择性和形式来区分。该中心建议通过整合六个主要研究人员的努力来解决这一假说，这些研究人员具有不同类型的小非编码RNA、多种模式生物、脂肪分泌和代谢的生物化学以及成像方面的专业知识。该中心将由四个项目和一个科学核心组成，致力于分离和鉴定细胞外与脂相关和无脂形式的小RNA。其目的将是在四个不同的环境中确定细胞外小RNA的来源、形式、目的地和功能：免疫刺激、原发癌症进展、转移性肿瘤生长和嗅神经元刺激。这些目标的完成预计将揭示共同的范例以及反映这些环境中不同驱动因素的不同机制。这项U19中心的提议具有非常重要的意义，因为它将在我们对细胞外小RNA代表什么及其下游功能的知识方面提供一个垂直飞跃。这一知识将使人们能够更深入地了解如何使用细胞外小RNA来跟踪疾病，以及如何操纵它们的水平以治疗疾病。