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Key factors in human ribosome biogenesis

人类核糖体生物发生的关键因素

基本信息

批准号：
9281554
负责人：
Susan J Baserga
金额：
$ 39.75万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9281554
关键词：
Animal Model Antisense Oligonucleotides Architecture Biogenesis Cell Nucleolus Cell physiology Cells Childhood Cirrhosis Collaborations Congenital Disorders Data Defect Development Diploidy Disease Dysmorphology Embryo Embryonic Development Etiology Eukaryotic Cell Exocrine pancreatic insufficiency Functional disorder Genetic Transcription Genetic Translation Goals Growth Health Hereditary Disease Housekeeping Human Human Genetics Laboratories Lead Link Liver Cirrhosis Malignant Neoplasms Maps Messenger RNA Methods Molecular Morbidity - disease rate Morphology Mutate Mutation North American Indians Organelles Organogenesis Orthologous Gene Pancytopenia Pathogenesis Population Process Proteins Publishing RNA Rana Ribosomal RNA Ribosomes Role Science Skin Abnormalities Testing Time Translations Tumorigenicity Work Xenopus Yeasts base biological adaptation to stress cancer therapy craniofacial design disease-causing mutation human disease human tissue in vivo insight knock-down lens novel organ growth protein complex public health relevance rRNA Precursor ribosome profiling tissue/cell culture

项目摘要

DESCRIPTION (provided by applicant): Ribosome biogenesis, beyond being a critical requirement for growth in all eukaryotic cells, has a broad impact on the etiology of numerous human disorders. Human genetic diseases caused by mutations in structural components of the ribosome or in factors required to make ribosomes in the cell nucleolus are called ribosomopathies. These largely congenital disorders present with a variety of morbidities: bone marrow failure, liver cirrhosis, pancreatic insufficiency, craniofacial dysmorphology and skin abnormalities. The pathogenesis of cancer, too, is linked to changes in nucleolar morphology and function. Because decreased nucleolar function can abrogate tumorigenicity, rRNA transcription and ribosome biogenesis have recently emerged as attractive new targets for anticancer therapies. Despite the clear impact of abnormalities in ribosome biogenesis on human disease, human ribosome biogenesis and the mechanisms behind the diverse ribosomopathies are just beginning to be investigated and elucidated. Our long-term goal is to understand how the architecture and function of the cell nucleolus relates to rare human genetic diseases and drives cancer. The objective of this application is to undertake a focused, in-depth approach to investigate the molecular basis of a putative ribosomopathy, North American Indian Childhood Cirrhosis (NAIC), and in doing so further probe how ribosomes are made in human cells. NAIC is a recessive congenital disease present in a First Nations Canadian population that maps to a R565W mutation in hUTP4/Cirhin, a protein first described in my laboratory in yeast. We propose: 1) To test the hypothesis that the mutation causative in NAIC leads to defective ribosome biogenesis in human cells; 2) To probe the mechanism by which defects in ribosome biogenesis caused by depletion or mutation of hUTP4/Cirhin lead to disease and 3) To test whether depletion or mutation of UTP4/Cirhin results in defects in organ development in vivo in the model organism, Xenopus tropicalis. These three Specific Aims are designed to pursue fundamental questions that will reveal how ribosomes are made in human cells and in an animal model through the lens of a human disease.

描述（由申请人提供）：核糖体生物发生除了是所有真核细胞生长的关键要求外，对许多人类疾病的病因学具有广泛影响。由核糖体的结构成分或细胞核仁中形成核糖体所需的因子突变引起的人类遗传疾病称为核糖体病。这些大部分先天性疾病存在多种发病率：骨髓衰竭、肝硬化、胰腺功能不全、颅面畸形和皮肤异常。癌症的发病机制也与核仁形态和功能的变化有关。由于核仁功能下降可以消除致瘤性，rRNA转录和核糖体生物合成最近成为抗癌治疗的有吸引力的新靶点。尽管核糖体生物发生异常对人类疾病有明显的影响，但人类核糖体生物发生和各种核糖体病背后的机制才刚刚开始研究和阐明。我们的长期目标是了解细胞核仁的结构和功能如何与罕见的人类遗传疾病和驱动癌症相关。本申请的目的是进行一个集中的，深入的方法来调查一个假定的核糖体病，北美印第安儿童肝硬化（NAIC）的分子基础，并在这样做进一步探测核糖体是如何在人类细胞中。NAIC是一种存在于加拿大原住民人群中的隐性先天性疾病，其映射到hUTP 4/Cirhin中的R565 W突变，该蛋白质首先在我的实验室酵母中描述。我们建议：1）测试NAIC中的突变病因导致人细胞中核糖体生物合成缺陷的假设; 2）探索由hUTP 4/Cirhin的缺失或突变引起的核糖体生物合成缺陷导致疾病的机制;和3）测试UTP 4/Cirhin的缺失或突变是否导致模式生物热带爪蟾（Xenopus tropicalis）体内器官发育缺陷。这三个特定目标旨在通过人类疾病的透镜来探索揭示核糖体在人类细胞和动物模型中是如何产生的基本问题。