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RNA通过与Argonaute家族蛋白结合并引导它们识别其靶标，在调节基因表达方面发挥着显着的作用。 Argonaute 的一个特定亚家族，名为 PIWI，与 PIWI 相互作用 RNA (piRNA) 结合，并促进迄今为止测试的所有动物的生育能力。 piRNA 和 PIWI 蛋白在生殖细胞中高度富集，PIWI 突变会导致不育并显着减少生殖细胞数量。此外，PIWI 样蛋白在多种癌症组织中过度表达，这种过度表达与不良预后有关。然而，piRNA 的生物发生以及 piRNA 调节生殖细胞和癌细胞的机制仍然很大程度上未知。在本提案中，我将使用线虫作为模型生物，通过具体的实验来解决有关 piRNA 通路的三个基本问题：piRNA 诱导基因沉默的分子机制是什么？ piRNA 调控的基因有哪些？最后，piRNA 生物发生和下游沉默涉及哪些成分？对这种进化上保守的途径的理解有可能为治疗不孕症和某些癌症提供新的治疗方法。