Role of MicroRNA-499 in the Heart

描述(由申请者提供)：这份建议书描述了一个为期5年的职业发展计划，其目标是让约瑟夫·谢博士为成为一名独立研究员做好准备。该计划将通过提供发育生物学方面的专业知识，在他的遗传学和儿科背景的基础上，促进他的职业发展。主要指导将由导师、加州大学旧金山分校格拉斯顿心血管疾病研究所所长迪帕克·斯里瓦斯塔瓦博士提供。他是公认的心脏开发领导者，并有培训独立科学家的记录。项目顾问委员会成员(MicroRNA生物学专家Michael McManus博士、心血管遗传学专家Didier Stainier博士和人类疾病小鼠模型专家Robert Nussbaum博士)将提供进一步培训。该研究计划将研究心力衰竭以及通过控制表征心力衰竭的基因表达变化来改变心力衰竭的可能性。假设是，被称为microRNAs的小型非编码RNA在心力衰竭中起着关键的调节作用，Shieh博士已经确定了人类心脏中含量最高的microRNAs之一，并确定它在肌肉发生中很重要。他开发了一种改变心脏中microRNA水平的小鼠模型，发现小鼠患上了心肌病。MicroRNA触发了心力衰竭中特有的基因表达模式，这表明这种microRNA正在控制这些途径。在这个项目中，将从三个方面评估mir-499在心脏中的功能：1)Shieh博士将确定mir-499和特定肌球蛋白基因在心脏中的表达模式，以将microRNA分配到特定的基因调控途径。2)他将确定mir-499水平是否会在疾病动物模型中加剧心力衰竭。3)他将确定mir-499在心力衰竭中发挥调节作用的途径。研究培训将得到发展生物学、遗传学和伦理学方面的正式教学计划的补充。加州大学旧金山分校儿科致力于谢医生的职业发展。加州大学旧金山分校和格莱斯顿大学为培养独立的内科科学家、促进合作研究和促进个人科学发展提供了良好的环境。

DESCRIPTION (provided by applicant): This proposal describes a 5-year-long career development program whose goal is to prepare Dr. Joseph Shieh for a role as an independent investigator. This program will promote his career development by building on his background in genetics and pediatrics by providing expertise in developmental biology. The principal guidance will be provided by the mentor, Dr. Deepak Srivastava, director of the Gladstone Institute for Cardiovascular disease at UCSF. He is a recognized leader in cardiac development and has a record of training independent scientists. The project advisory committee members (Dr. Michael McManus, an expert on microRNA biology; Dr. Didier Stainier, an expert in cardiovascular genetics; and Dr. Robert Nussbaum, an expert in mouse models of human disease) will provide further training. The research program will address heart failure and the potential to alter heart failure by controlling the gene expression changes that characterize failure. The hypothesis is that the small non-coding RNAs called microRNAs play a key regulatory role in heart failure, and Dr. Shieh has identified one of the most highly enriched microRNAs in the human heart and determined that it is important in myogenesis. He developed a mouse model that alters the microRNA level in the heart and found that the mice develop cardiomyopathy. The microRNA triggers characteristic gene expression patterns that are seen in heart failure, suggesting this microRNA is controlling these pathways. In this project, the function of mir-499 in the heart will be assessed in three aims: 1) Dr. Shieh will determine the expression patterns of mir-499 and specific myosin genes in the heart to assign the microRNA to a specific gene regulatory pathway. 2) He will determine whether mir-499 levels exacerbate heart failure in animal models of disease. 3) He will determine the pathway by which mir-499 exerts its regulatory role in heart failure. Research training will be complemented by a formal didactic program in developmental biology, genetics, and ethics. The UCSF Pediatrics Department is committed to Dr. Shieh's career development. UCSF and Gladstone provide an outstanding environment for training independent physician scientists, promoting collaborative research and fostering individual scientific development.