Regulation of Systemic RNA Interference in the Nematode C. elegans

线虫系统性 RNA 干扰的调控. 线虫

• 批准号: 8294716
• 负责人: Jennifer Sung Whangbo
• 金额: $ 13.23万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-16 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294716
• 关键词: Address; Biological; Biological Models; Biology; Boston; Caenorhabditis elegans; Cells; Clinical; Clinical Trials; Connexins; Cytoplasm; Development; Development Plans; Double-Stranded RNA; Eukaryota; Family; Family member; Fire - disasters; Foundations; Gap Junctions; Gene Expression Regulation; Gene Silencing; Genes; Genetic Screening; Growth; Hematology; Hematopoietic Stem Cell Transplantation; Human; Human Cell Line; Institution; Laboratories; Macular degeneration; Mammalian Cell; Mammals; Mediating; Medicine; Mentors; Mentorship; Methods; Molecular; Molecular Genetics; Molecular and Cellular Biology; Movement; Mus; Mutation; Nature; Nematoda; Nobel Prize; Organism; Pathway interactions; Pediatric Hospitals; Pharmaceutical Preparations; Phase; Physicians; Positioning Attribute; Principal Investigator; Process; Property; Proteins; RNA; RNA Interference; RNA Interference Pathway; RNA Transport; Regulation; Reporting; Research; Respiratory syncytial virus; Role; Scientist; Screening procedure; Signal Transduction; Speed; Sterility; Surveys; System; Therapeutic; Tissues; Training; Translational Research; Universities; Vascular Endothelial Growth Factors; base; career; career development; cell type; experience; gene discovery; gene function; gene therapy; genetic analysis; in vivo; insight; intercellular communication; member; novel; oncology; positional cloning; programs; small molecule; tool; uptake

The candidate presents a 5-year career development plan that seeks to advance the understanding of how RNA-mediated silencing signals are transported between cells, while establishing an academic career in hematopoietic stem cell transplantation (HSCT) and gene-based therapies. The candidate will build on her strong foundation in molecular genetics to gain expertise in the RNA interference (RNAi) field under the mentorship of Dr. Craig Hunter, a leader in systemic RNAi biology. In addition, the candidate will develop further clinical acumen in HSCT while participating in the establishment of a gene therapy program at Children's Hospital Boston under the guidance of Dr. David Williams. As a pioneer in the gene therapy field with extensive experience in translational research, Dr. Williams is uniquely positioned to support the proposal as a co-mentor. The plan will be conducted in the Department of Molecular and Cellular Biology at Harvard University, a founding institution of modern biology; and in the Division of Hematology/Oncology at Children's Hospital Boston, which has a distinguished record for training physician-scientists. This proposal is timely as RNAi has advanced from Nobel prize-winning discovery in 1998 to therapeutics with exceptional speed. RNAi-based therapies targeting the respiratory syncytial virus and the VEGF pathway for macular degeneration are already in clinical trials. Major barriers to successful RNAi delivery in vivo include targeting the appropriate cell type and promoting cellular uptake and release of the drug into the cytoplasm. The study of systemic RNAi in the model system Caenorhabditis elegans will provide important insights for the delivery of RNAi-based therapies in humans. For example, discovery of the widely conserved SID-1 doublestranded RNA (dsRNA) channel in C. elegans has led to strategies for enhanced delivery of dsRNA in mammalian cells. The specific aims of this proposal are: 1) to conduct a screen to identify and characterize new genes required for the spread of RNA-mediated silencing signals and 2) to analyze the role of gap junction proteins in systemic RNAi. Execution of these aims will elucidate fundamental mechanisms underlying the import and export of RNA-mediated silencing signals between cells and tissues.

候选人提出了一个5年的职业发展计划，旨在促进对如何 RNA介导的沉默信号在细胞之间传输，同时建立了一个学术生涯， 造血干细胞移植（HSCT）和基因治疗。候选人将在她的基础上 在分子遗传学的坚实基础，以获得在RNA干扰（RNAi）领域的专业知识，根据 克雷格亨特博士的指导下，在系统RNAi生物学的领导者。此外，候选人将发展 进一步提高HSCT的临床敏锐度，同时参与建立基因治疗计划， 波士顿儿童医院在大卫威廉姆斯医生的指导下。作为基因治疗领域的先驱 凭借在转化研究方面的丰富经验，威廉姆斯博士具有独特的优势，可以支持 作为一个共同导师的建议。该计划将在分子和细胞生物学系进行， 哈佛大学，现代生物学的创始机构;以及血液学/肿瘤学系， 波士顿儿童医院，在培训医生科学家方面有着杰出的记录。这项建议 是及时的，因为RNAi已经从1998年获得诺贝尔奖的发现发展到具有特殊疗效的治疗方法， 速度靶向呼吸道合胞病毒和VEGF通路的基于RNAi的黄斑病变治疗 已经在临床试验中。成功体内递送RNAi的主要障碍包括靶向 合适的细胞类型和促进细胞摄取和药物释放到细胞质中。的 在模式系统秀丽隐杆线虫中的系统性RNAi研究将为 在人类中提供基于RNA干扰的疗法。例如，发现了广泛保守的SID-1双链 RNA（dsRNA）通道。elegans已经导致了增强dsRNA递送的策略， 哺乳动物细胞这项建议的具体目标是：1）进行筛查， RNA介导的沉默信号传播所需的新基因; 2）分析缺口的作用 系统性RNAi中的连接蛋白。实现这些目标将阐明基本机制 作为细胞和组织之间RNA介导的沉默信号的输入和输出的基础。