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Forward Genetic Analysis of Human Nuclear Long Non-Coding RNAs

人核长非编码 RNA 的正向遗传分析

基本信息

批准号：
10348700
负责人：
ANDREI ALEXANDROV
金额：
$ 27.64万
依托单位：
CLEMSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-10 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10348700
关键词：
Address Antiviral Therapy Biochemical Biogenesis Candidate Disease Gene Cell Line Cells Centers of Research Excellence Color Complex Disease Down-Regulation Endocrine Fluorescence Foundations Genes Genetic Goals Human Human Genetics Human Herpesvirus 8 Immune Individual Investigation Libraries Lytic MALAT1 gene MEN1 gene Malignant Neoplasms Methods Molecular Neoplasms Neuronal Differentiation Nuclear Nuclear Export Pathogenicity Pathway interactions Poly A Poly(A)+ RNA Post-Transcriptional Regulation Production RNA Refractory Regulation Reporter Role Technology Therapeutic Therapeutic Intervention Transcript Untranslated RNA Viral Virus Diseases anti-cancer base cancer therapy design developmental disease embryonic stem cell forward genetics gammaherpesvirus gene discovery gene network genetic analysis genome-wide genome-wide analysis high throughput screening human disease human embryonic stem cell in vivo knowledge of results particle screening stem cell differentiation therapeutic target triple helix

项目摘要

PROJECT SUMMARY Certain human nuclear long non-coding RNAs (lncRNAs) represent well-established promising targets for the treatment of cancer, developmental and viral diseases; manipulating their levels is expected to provide therapeutic interventions for various human disorders. However, due to the lack of a reliable high-throughput screening technology to quantify nuclear lncRNA levels, human pathways of nuclear lncRNA biogenesis, regulation, and surveillance have been refractory to forward genetic identification. We developed an approach that enables the first successful forward genetic interrogation of the pathways of biogenesis and surveillance of the nuclear lncRNA MALAT1 in human cells. We identified human nuclear complexes required for MALAT1 3′ end surveillance and components required for MALAT1-associated small cytoplasmic RNA (mascRNA) maturation, as well as numerous candidate genes that require further investigation. We propose to expand this approach and perform comprehensive forward genetic identification of human nuclear pathways acting on the following lncRNAs: (i) cancer-associated lncRNA MALAT1, (ii) multiple endocrine neoplasia transcript 1 (MEN- β), which is up-regulated upon embryonic stem cell and neuronal differentiation, and (iii) polyadenylated nuclear lncRNA PAN, required for lytic production of new viral particles by the Kaposi’s sarcoma-associated herpesvirus (KSHV). This study is aimed to identify human pathways and regulatory networks acting on nuclear lncRNAs and uncover new targets for potential anti-cancer and anti-viral therapies.

项目总结