Investigating microRNA Function in Homeostasis, Regeneration and Cancer

研究 microRNA 在稳态、再生和癌症中的功能

基本信息

批准号：
10678921
负责人：
Andrea Ventura
金额：
$ 50.92万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10678921
关键词：
Acute Address Adult Affect Aging Alleles Applications Grants Binding Biogenesis Biological Process Cancer cell line Cells Chronic Code Complex Cues Development Doxycycline Ensure Gene Expression Gene Expression Regulation Gene Fusion Genes Genetic Transcription Genetically Engineered Mouse Goals Homeostasis In Vitro Infection Inflammation Injury Liver Maintenance Malignant Neoplasms Mammals Maps Mediating Messenger RNA MicroRNAs Mouse Strains Mus Natural regeneration Normal tissue morphology Nucleotides Partner in relationship Pathway interactions Phenotype Population Process Protein Family Proteins Repression Research Resolution Ribonucleoproteins Role Series Site Testing Time Tissues Transgenic Mice Transgenic Organisms Untranslated RNA Work anti-cancer cell type experimental study gain of function gene repression human cancer mouse model in vivo innovation insight intestinal epithelium loss of function member novel novel strategies posttranscriptional prevent protein degradation recruit small molecule inhibitor stem cell population tissue regeneration tumor tumor initiation tumor progression tumorigenesis

Acute Address Adult Affect Aging Alleles Applications Grants Binding Biogenesis Biological Process Cancer cell line Cells Chronic Code Complex Cues Development Doxycycline Ensure Gene Expression Gene Expression Regulation Gene Fusion Genes Genetic Transcription Genetically Engineered Mouse Goals Homeostasis In Vitro Infection Inflammation Injury Liver Maintenance Malignant Neoplasms Mammals Maps Mediating Messenger RNA MicroRNAs Mouse Strains Mus Natural regeneration Normal tissue morphology Nucleotides Partner in relationship Pathway interactions Phenotype Population Process Protein Family Proteins Repression Research Resolution Ribonucleoproteins Role Series Site Testing Time Tissues Transgenic Mice Transgenic Organisms Untranslated RNA Work anti-cancer cell type experimental study gain of function gene repression human cancer mouse model in vivo innovation insight intestinal epithelium loss of function member novel novel strategies posttranscriptional prevent protein degradation recruit small molecule inhibitor stem cell population tissue regeneration tumor tumor initiation tumor progression tumorigenesis

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项目摘要

ABSTRACT Precise temporal and spatial control of gene expression is essential to ensure normal development and homeostasis and is achieved through multiple regulatory mechanisms acting at every step from gene transcription to protein degradation. MicroRNAs (miRNAs), constitute a large class of highly conserved regulatory short non-coding RNAs that modulate gene expression at the post-transcriptional level. Mechanistically, miRNAs repress their targets as part of a large multicomponent ribonucleoprotein known as the miRNA-Induced Silencing Complex (miRISC), which include Argonaute proteins (AGO) and members of the TNRC6 family of proteins. How miRISC assembly and activity are regulated in vivo remains poorly understood and until recently it was tacitly assumed that miRNAs are constitutively active in all cell types. Recent work from several groups, including ours, has challenged this assumption, revealing that assembly of the miRISC is tightly regulated in vivo, and suggesting the possibility that in many adult tissues and in quiescent cells the bulk of miRNA-bound AGO proteins are not bound to target mRNAs, and are not engaged in their repression. Why many adult tissues and quiescent cells contain high levels of functionally inactive miRNAs and whether, in addition to mitogenic cues, other perturbations—including cancer, aging, infection, and inflammation—regulate miRISC assembly and activity are two major unanswered questions in the field and the main focus of this grant proposal. As a first step to address these two questions we propose a series of experiment that take advantage of a novel genetically engineered mouse strain we have recently generated that allows to control miRISC assembly in vivo in a temporally and spatially controlled fashion. We will use this novel mouse strain to determine the requirement for miRISC activity during normal tissue homeostasis, in development, and during tissue regeneration (Aim 1). In Aim 2, we will use it to directly test the hypothesis that miRISC activity is required for tumor progression and tumor maintenance in vivo and we will determine the potential of miRISC inhibition as a novel anticancer strategy. Finally, in Aim 3 we will take advantage of a novel mouse strain we have developed to gain mechanistic insights into how miRNAs control these essential processes. Successful completion of this project will greatly advance our understanding of the role of miRNA-mediated gene repression in mammals and could lead to the development of novel anti-cancer strategies.

抽象的基因表达的精确暂时和空间控制对于确保正常发育和体内稳态，是通过在基因的每一步都起作用的多种调节机制来实现的转录蛋白质降解。 microRNA（miRNA），构成了一大批高度保守调节短的非编码RNA在转录后水平调节基因表达。从机械上讲，miRNA作为大型多组分核糖核蛋白的一部分反映其靶标 miRNA引起的沉默复合物（Mirisc），其中包括Argonaute蛋白（AGO）和成员 TNRC6蛋白质家族。在体内如何调节Mirisc组装和活动的理解仍然很差，直到最近才默认假设miRNA在所有细胞类型中持续活跃。来自几个小组的最新工作，包括我们的人对这一假设提出了质疑，揭示了米里斯的组装在体内受到严格的调节，并且表明在许多成年组织和静态细胞中，大部分miRNA结合了蛋白质不可能靶向mRNA，也不参与其表达。为什么许多成年组织和静态细胞都包含高水平的功能性miRNA，而除了有丝分裂提示，其他扰动（包括癌症，衰老，感染和）炎症 - 调节米斯利斯议会和活动是该领域的两个主要未解决问题这是该赠款提案的主要重点。作为解决这两个问题的第一步，我们提出了一系列实验，以利用新颖我们最近生成的基因工程小鼠菌株可以在体内控制Mirisceshbly 以暂时和空间控制的方式。我们将使用这种新颖的鼠标菌株来确定需求对于正常组织稳态，发育和组织再生期间的Mirisc活性（AIM 1）。在AIM 2中，我们将使用它直接检验以下假设：肿瘤进展和体内肿瘤维持，我们将确定Mirisc抑制作用作为一种新型抗癌策略的潜力。最后，在目标3中，我们将利用一种新的小鼠菌株来获得机械洞察力 miRNA如何控制这些基本过程。成功完成该项目将大大提高我们对miRNA介导的基因作用的理解哺乳动物的抑制作用，可能导致新型抗癌策略的发展。