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Structural Biology Studies of Ribosome Biogenesis Network

核糖体生物发生网络的结构生物学研究

基本信息

批准号：
10389719
负责人：
Hong Li
金额：
$ 1.73万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-10 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10389719
关键词：
3-Dimensional Alzheimer&apos s Disease Antineoplastic Agents Biochemical Biochemical Genetics Biogenesis Biological Assay Biophysics Cell Death Cell Nucleolus Cells Client Clinical Trials Complex Cryoelectron Microscopy Data Disease Enzymes Eukaryotic Cell Event Genetic Diseases Heat-Shock Proteins 90 Human Laboratories Link Malignant Neoplasms Mass Spectrum Analysis Methods Molecular Molecular Chaperones Molecular Machines Morphology Nerve Degeneration Pathway interactions Pharmaceutical Preparations Pharmacology Physiological Process Production Protein Biochemistry Protein Biosynthesis Proteins Research Resistance development Ribosomes Risk Role Scientist Structure Therapeutic X-Ray Crystallography anti-cancer base biophysical techniques design drug action insight molecular site protein folding structural biology success yeast genetics

项目摘要

Description: Ribosome is the evolutionarily conserved molecular machine responsible for synthesis of proteins. In eukaryotic cells, ribosome is produced in a biophysically distinct subnuclear compartment, the nucleolus, through a cascade of energy-driven events. This process underlies a number of genetic diseases and is a major target for anti-cancer and anti-neurodegeneration therapeutics. However, the physical interactions of the network required for this process remain largely uncharacterized. This application will characterize a key molecular complex called R2TP that acts early in ribosome production by facilitating assembly of several ribosome production enzymes. R2TP has a wide client base, collaborates with a general protein folding chaperone, heat shock protein 90 (Hsp90), and delivers clients to the nucleolus. The Li laboratory uses a combination of structural biology, biochemical, and genetics methods to provide functional insights on R2TP and its impact on ribosome production. Exceptionally detailed three-dimensional views of R2TP itself and those R2TP acts upon will be obtained and analyzed along with the available functional data. Two specific aims are designed to 1) establish the structure and function cycle of R2TP; 2) elucidate the physiological role of R2TP. Results of this study will identify new molecular sites for developing anti-cancer and anti-neurodegenerative drugs through controls of ribosome production and degradation. The Li laboratory has assembled a team of scientists with complementary expertise in x-ray crystallography, high-throughput electron cryomicroscopy, mass spectrometry, biophysics, protein biochemistry, and yeast genetics in order to maximize the chance of successes while mitigating risks. Relevance: Aberrant nucleolar morphology and function have been linked to cancers and Alzheimer's disease in human. Correspondingly, R2TP and its client proteins have been identified as key regulators of nucleolar morphology. Whereas more than fifteen types of anti-cancer drugs have been investigated or in clinical trials that target molecules involved in this pathway, none is known for anti-neurodegeneracy. Though effective in cell-death assays, the pharmacological basis of many compounds remains to be explained and some develop resistance in cells. The proposed research provides platforms for explaining the actions of the existing drugs while discovering new ones.

核糖体是进化上保守的分子机器，用于蛋白质的合成。在真核细胞中，核糖体是在一个生物蛋白酶促反应中产生的。不同的亚核区室，核仁，通过级联的能量驱动事件这一过程是许多遗传疾病的基础，也是治疗的主要目标。抗癌和抗神经变性治疗。然而，物理相互作用这一过程所需的网络仍然在很大程度上没有特征。本申请将描述一种称为R2 TP的关键分子复合物，它在核糖体早期起作用，通过促进几种核糖体生产酶的组装来生产。R2TP 广泛的客户群，与一般蛋白质折叠伴侣，热休克蛋白90（Hsp 90），并将客户端递送到核仁。Li实验室使用一种结构生物学、生物化学和遗传学方法的组合， R2 TP的功能及其对核糖体产生的影响。格外 R2 TP本身以及R2 TP作用于的那些实体的详细三维视图将在与可用的功能数据一起沿着进行分析。两个具体目标是旨在1）建立R2 TP的结构和功能循环; 2）阐明 R2 TP的生理作用这项研究的结果将确定新的分子位点，通过控制核糖体开发抗癌和抗神经退行性疾病药物生产和降解。Li实验室已经组建了一个科学家团队，在X射线晶体学、高通量电子低温显微镜、质谱、生物物理学、蛋白质生物化学和酵母遗传学，以最大限度地提高成功的机会，同时降低风险。相关性：异常的核仁形态和功能与癌症有关和阿尔茨海默病的关系。相应地，R2 TP及其客户蛋白具有被认为是核仁形态的关键调节因子。而超过15个已经研究了多种类型的抗癌药物，或在临床试验中，虽然这些分子参与了这一途径，但没有一种已知具有抗神经变性作用。虽然尽管在细胞死亡测定中是有效的，但许多化合物的药理学基础仍然是有些会在细胞中产生耐药性。该研究提供了在发现新药的同时解释现有药物作用的平台。