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Molecular Genetic Analysis of Extracellular RNAs in C. Elegans

线虫细胞外 RNA 的分子遗传学分析

基本信息

批准号：
10160923
负责人：
CRAIG Patrick HUNTER
金额：
$ 39.25万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10160923
关键词：
Alleles Animal Model Animals Biogenesis Biological Markers Biological Process Bypass Caenorhabditis elegans Cells Characteristics Complex DNA DNA Repair Pathway DNA Sequence Destinations Double-Stranded RNA Environment Epigenetic Process Extracellular Space Family Future Generations Gene Rearrangement Generations Genes Genetic Genetic Epistasis Genetic Recombination Genotype Goals Height Heritability Individual Inherited Investigation Laws Measures Medicine Methods Modernization Modification Molecular Molecular Genetics Monitor Mutagens Nature Nematoda Nucleic Acids Organism Parents Pathway interactions Phenotype Physiological Population Prevalence Process Proteins Publishing RNA RNA Interference RNA Transport Reproducibility Research Research Project Grants Role Running Siblings Signal Transduction Small Interfering RNA Societies Source Specificity Stress Testing Therapeutic Intervention Time Tissues Variant base disorder risk environmental change epigenetic silencing extracellular genetic analysis imprint insight mutant offspring protein transport symposium targeted delivery therapeutic RNA tool trafficking trait transgenerational epigenetic inheritance transmission process whole genome

项目摘要

Project Summary Siblings resemble each other more than expected based on the genes that they inherit from their parents. This unexpected finding derives from recent studies that measure the association between genotype (variations in DNA sequence) and traits (e.g. height or disease risk) among large populations of unrelated people. This discrepancy indicates that parents may transmit extra, non-gene, information to their offspring. This non-gene information is called epigenetics, literally “beyond” genetics, and is a well-established field, but convention accepts that epigenetic information is erased each generation. Studies in the emerging field of transgenerational epigenetic inheritance (TEI) are challenging this convention. However, little is known about how inherited epigenetic information is encoded, how it responds to environmental conditions, and how it is transmitted between generations. Because inherited epigenetic information is malleable and may account for up to half the inheritance of disease risk, the answers to these questions will have an enormous impact on society and medicine. Investigating how TEI is established, maintained, and transmitted is challenging: it requires analysis of multiple generations and studies to date indicate that its effects are impermanent, fading with successive generations. The proposed research uses the nematode C. elegans to investigate TEI. C. elegans has numerous experimental advantages for studying TEI, primary among them is a fast, three-day, generation time and a powerful molecular tool called RNA interference (RNAi), which can direct the silencing of any gene. One special characteristic of RNAi in C. elegans is that the silencing signals, a form of RNA, can move between cells and tissues, including to the germline, thus transmitting silencing to future generations. Published studies from the applicants group characterized an RNAi-dependent mechanism of TEI, showing that epigenetic silencing could be maintained for nearly 20 generations. To further explore the transmission of TEI in C. elegans the applicant proposes (Aim 1) to investigate the activity and selectivity of proteins that transport RNA between cells; (Aim 2) to characterize the biogenesis and transport of endogenous mobile RNAs and to investigate their role in epigenetic inheritance; and (Aim 3) to investigate the prevalence, mechanisms, and utility of TEI for organismal adaption to environmental change.

项目概要根据从父母那里继承的基因，兄弟姐妹之间的相似程度超出了预期。这出乎意料的发现源自最近测量基因型之间关联的研究（基因型的变异） DNA 序列）和大量无关人群的特征（例如身高或疾病风险）。这差异表明父母可能会将额外的非基因信息传递给后代。这个非基因信息被称为表观遗传学，字面意思是“超越”遗传学，是一个成熟的领域，但惯例承认表观遗传信息每一代都会被删除。新兴领域的研究跨代表观遗传（TEI）正在挑战这一惯例。然而，鲜为人知关于遗传的表观遗传信息是如何编码的，它如何响应环境条件，以及它如何是在代际间传承的。因为遗传的表观遗传信息是可塑的并且可以解释高达一半的疾病风险会遗传，这些问题的答案将对社会和医学。研究 TEI 是如何建立、维护和传输的具有挑战性：它需要分析迄今为止的多代研究表明，其影响是无常的，会随着连续发生而逐渐消失。几代人。拟议的研究使用线虫秀丽隐杆线虫来研究 TEI。线虫有研究 TEI 的众多实验优势，其中最主要的是三天的快速生成时间还有一种强大的分子工具，称为RNA干扰（RNAi），它可以指导任何基因的沉默。一线虫中 RNAi 的特殊特征是沉默信号（RNA 的一种形式）可以在细胞和组织，包括生殖系，从而将沉默传递给后代。已发表的研究来自申请人小组的特征是 TEI 的 RNAi 依赖性机制，表明表观遗传沉默可以维持近20代。进一步探讨TEI在C. 申请人提出的线虫（目标 1）研究运输 RNA 的蛋白质的活性和选择性细胞之间；（目标 2）表征内源性移动 RNA 的生物发生和运输，并研究它们在表观遗传中的作用；（目标 3）调查患病率、机制和 TEI 在生物体适应环境变化方面的效用。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Natural RNA interference directs a heritable response to the environment.

DOI：
10.1038/srep07387
发表时间：
2014-12-09
期刊：
Scientific reports
影响因子：
4.6
作者：
Schott D;Yanai I;Hunter CP
通讯作者：
Hunter CP

SIDT2 Transports Extracellular dsRNA into the Cytoplasm for Innate Immune Recognition.

DOI：
10.1016/j.immuni.2017.08.007
发表时间：
2017-09-19
期刊：
Immunity
影响因子：
32.4
作者：
Nguyen TA;Smith BRC;Tate MD;Belz GT;Barrios MH;Elgass KD;Weisman AS;Baker PJ;Preston SP;Whitehead L;Garnham A;Lundie RJ;Smyth GK;Pellegrini M;O'Keeffe M;Wicks IP;Masters SL;Hunter CP;Pang KC
通讯作者：
Pang KC

Vampiric isolation of extracellular fluid from Caenorhabditis elegans.

从秀丽隐杆线虫中分离出细胞外液的吸血鬼。