Investigating the Biogenesis and Function of piRNAs in Germline Development

研究 piRNA 在种系发育中的生物发生和功能

基本信息

批准号：
8321723
负责人：
Heng-Chi Lee
金额：
$ 5.39万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8321723
关键词：
Address Animal Model Animal Testing Apoptosis Binding Biochemical Biogenesis Biological Markers Caenorhabditis elegans Cell Count Cell Maintenance Cells Cleaved cell Complex Development Disease Family Fertility Functional RNA Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Screening Genets Germ Cell Cancers Germ Cells Infertility Lead Link Malignant Neoplasms Mediating Messenger RNA Molecular Molecular Genetics Mutation Names Nematoda Outcome Pathway interactions Play Protein Family Proteins Proteomics RNA RNA Interference RNA Sequences Reporter Role Small Interfering RNA Small RNA Staging Stem cells Sterility T-cell acute lymphocytic leukemia 1 protein Tissues Transcript Transgenic Organisms cancer cell chromatin immunoprecipitation genome-wide malignant breast neoplasm member mutant novel novel therapeutic intervention novel therapeutics outcome forecast overexpression research study treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): Small RNAs play remarkable roles in regulating gene expression by binding to Argonaute family proteins and guiding them to recognize their targets. A specific subfamily of Argonaute, named PIWI, binds PIWI-interacting RNA (piRNA) and promotes fertility in all animals tested to date. piRNAs and PIWI proteins are highly enriched in germ cells, and PIWI mutations lead to sterility and dramatically reduced germ-cell numbers. In addition, PIWI-like proteins are overexpressed in several cancer tissues and this overexpression has been linked to poor prognosis. However, the biogenesis of piRNAs, as well as the mechanism by which piRNAs regulate germ cell and cancer cell, remain largely unknown. In this proposal I will use specific experiments to address three fundamental questions about piRNA pathways using nematode C. elegans as model organism: What is the molecular mechanism of piRNA-induced gene silencing? What are the genes regulated by piRNAs? Finally, what are the components involved in piRNA biogenesis and downstream silencing? The understanding of this evolutionally conserved pathway has potential to provide novel therapeutic approaches for treatment of infertility and certain cancers.

描述（由申请人提供）：小型RNA通过与Argonaute家族蛋白结合并指导它们识别其靶标，在调节基因表达中起着显着的作用。 Argonaute的特定亚科，名为Piwi，结合了PIWI相互作用的RNA（PIRNA），并促进迄今为止所有测试的动物的生育能力。 PIRNA和PIWI蛋白在生殖细胞中高度富集，PIWI突变导致不育和大幅度降低的种系数量。此外，在几种癌症组织中，PIWI样蛋白过表达，这种过表达与预后不良有关。然而，PIRNA的生物发生以及PIRNA调节生殖细胞和癌细胞的机制，在很大程度上尚不清楚。在此提案中，我将使用特定的实验来解决有关PIRNA途径的三个基本问题，该问题使用线虫C. elegans作为模型生物：PIRNA诱导的基因沉默的分子机制是什么？ PIRNA调节的基因是什么？最后，PiRNA生物发生和下游沉默涉及哪些组成部分？对这一进化保守的途径的理解有可能提供新颖的治疗方法来治疗不育和某些癌症。