Key factors in human ribosome biogenesis

 描述(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，还对许多人类疾病的病因学产生了广泛的影响。由核糖体结构成分突变或使核糖体进入细胞核仁所需的因子突变而引起的人类遗传病称为核糖病。这些以先天性疾病为主的疾病表现出各种疾病：骨髓衰竭、肝硬变、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。由于核仁功能降低可以消除肿瘤的致瘤性，rRNA转录和核糖体生物发生最近成为抗癌治疗的新靶点。尽管核糖体生物发生的异常对人类疾病有明显的影响，但人类核糖体的生物发生以及各种核糖体疾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与罕见的人类遗传病和驱动癌症的关系。这项应用的目的是采取一种有针对性的、深入的方法来研究一种可能的核糖体病--北美印第安人儿童期肝硬变(NAIC)的分子基础，并在此过程中进一步探索核糖体是如何在人类细胞中制造的。NAIC是一种隐性先天性疾病，存在于加拿大原住民人群中，它与hUTP4/Cirhin的R565W突变有关，这是一种在我的实验室首次在酵母中描述的蛋白质。我们建议：1)验证NAIC突变导致人类细胞核糖体生物发生缺陷的假设；2)探讨hUTP4/Cirhin缺失或突变导致核糖体生物发生缺陷导致疾病的机制；3)测试UTP4/Cirhin缺失或突变是否会导致模式生物热带爪哇体内器官发育缺陷。这三个具体目标旨在通过人类疾病的透镜来探索基本问题，这些问题将揭示核糖体是如何在人类细胞和动物模型中制造的。

 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.