Networks, Pathways and Dynamics of Lysine Modification

赖氨酸修饰的网络、途径和动力学

• 批准号: 8313967
• 负责人: Jef D BOEKE
• 金额: $ 351.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313967
• 关键词: Acetylation; Address; Affect; Aging; Algorithms; Alleles; Anaphase; Antibodies; Area; Automobile Driving; Biological; Biological Assay; Biological Markers; Biological Process; Biology; Biomedical Engineering; Biophysics; Budgets; Cell Cycle; Cell Cycle Progression; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chemicals; Chicago; Chromatin; Clinical; Clip; Collaborations; Complement; Complex; DNA; Data Set; Deacetylation; Development; Digestion; Diploidy; Disease; Dissociation; Electron Transport; Enzymes; Epidermal Growth Factor Receptor; Epigenetic Process; Equilibrium; Essential Genes; Factor Analysis; Faculty; Family; Fatty acid glycerol esters; Funding; Gene Expression; Gene Expression Profile; Gene Family; Genes; Genetic; Genetic Medicine; Genetic Recombination; Genome; Goals; Health; Hematoxylin and Eosin Staining Method; Histone Deacetylase; Histone H3; Histone H4; Histones; Human; Hydrolase; Image; In Vitro; Institutes; Instruction; Internships; Isomerism; Kinetics; Knock-out; Lead; Learning; Libraries; Life; Ligands; Lung Neoplasms; Lysine; Malignant neoplasm of lung; Maps; Marriage; Mass Spectrum Analysis; Massachusetts; Measurement; Measures; Mediating; Memorial Sloan-Kettering Cancer Center; Metabolic; Metaphase; Methods; Methylation; Microarray Analysis; Microfluidic Microchips; Microfluidics; Mitosis; Mitotic; Modification; Molecular; Molecular Biology; Molecular Genetics; Monitor; Mono-S; Mutate; Mutation; Natural regeneration; Nature; Neurons; Nucleosomes; Organism; Pathway interactions; Pattern; Peptide antibodies; Peptides; Pharmacology; Phosphorylation; Phosphotransferases; Plastics; Play; Post-Translational Protein Processing; Process; Prophase; Protein Microchips; Protein p53; Proteins; Proteome; Proteomics; Public Health Schools; Puerto Rico; Reading; Reagent; Receptor Activation; Recombinant DNA; Regulation; Relative (related person); Reporter; Research Personnel; Resistance; Resources; Role; Route; Saccharomyces cerevisiae; Science; Series; Signal Pathway; Signal Transduction; Sirtuins; Sister Chromatid; Site; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Staging; Stimulus; Structure; Students; Substrate Specificity; System; Technology; Temperature; Time; Training; Triciribine Phosphate; Ubiquitin; Universities; Work; Yeasts; abstracting; analog; base; cell type; design; fascinate; genetic analysis; high risk; histone modification; in vivo; innovation; intein; interest; mass spectrometer; medical schools; member; mutant; new technology; novel; novel strategies; pre-clinical; professor; protein function; receptor; response; segregation; small hairpin RNA; synthetic peptide; technology development; temperature sensitive mutant; tool

PROJECT SUMMARY (See instructions): Protein modification on histone lysines is critical for controlling gene expression, which itself controls the variable and plastic expression of the proteome in diverse cell types. Modifications on lysine are chemically diverse and include acetylation, methylation, ubiquitylation and sumoylation. We and others have discovered acetyl- and methyl-lysines in many other proteins, and only some directly control gene expression; many are critical regulatory metabolic enzymes. Ubiquitylation controls the life and death of most proteins, and other protein functions. The pathways regulating diverse modifications on lysines are remarkably complex; much remains to be learned. The network of and dynamic interactions among these modification pathways is even more complex; many lysine-modifying proteins are encoded by multi-gene families, have redundant activities, and multiple substrates, only some of which are known. Cross-talk between modifications provides an extra layer of regulation. We have developed genetic, protein chip, chemical, microfiuidic and computational approaches to decrypt and abstract the complex networks defined by these signaling pathways and monitor how they change over time. This proposal extends many unique technologies developed in the last budget period, with a special focus on adapting these technologies to monitoring dynamic proteomic changes occurring in response to a range of biological stimuli. These newer approaches are complemented in this Technology Center for Networks and Pathways by application of innovative mass spectrometry technologies, including sensitive and diverse technologies for quantifying dynamics of lysine modification in cells. The yeast metabolic cycle, integrated with cell cycling and DNA integrity is a fascinating dynamic cycle that will be studied in detail with several of the technologies. Diverse Driving Biological Projects centered on lysine acetylation, methylation, ubiquitylation and SUMOylafion, as well as advanced Training efforts. Including an internship for students in Puerto Rico, are integrated with the Technology Development aspects of the proposal. Technologies and resources are actively disseminated via multiple routes; both static and dynamic proteomics datasets will be centrally warehoused/disseminated.

项目摘要（请参阅说明）： 组蛋白赖氨酸的蛋白质修饰对于控制基因表达至关重要，基因表达本身可以控制各种细胞类型中蛋白质组的可变和塑性表达。赖氨酸的修饰是化学多样的，包括乙酰化，甲基化，泛素化和sumoylation。我们和其他人在许多其他蛋白质中发现了乙酰基和甲基赖氨酸，只有一些直接控制基因表达。许多是关键的调节代谢酶。泛素化控制大多数蛋白质的生命和死亡以及其他蛋白质功能。调节赖氨酸各种修饰的途径非常复杂。还有很多要学习的。这些修改途径之间的动态交互网络更加复杂。许多赖氨酸调节蛋白由多基因家族编码，具有冗余活动和多个底物，其中只有一些是已知的。修改之间的串扰提供了额外的调节层。我们已经开发了遗传，蛋白质芯片，化学，微膜和计算方法来解密和抽象这些信号通路定义的复杂网络，并监视它们如何随时间变化。该提案扩展了在上一个预算期间开发的许多独特技术，特别着重于将这些技术调整以监测响应一系列生物学刺激而发生的动态蛋白质组学变化。通过应用创新的质谱技术，包括量化细胞中赖氨酸修饰的动力学，包括敏感和多样化的技术，包括该技术中心的网络和途径技术中心，对这些较新的方法进行了补充。与细胞循环和DNA完整性集成的酵母代谢循环是一个引人入胜的动态循环，将与几种技术进行详细研究。以赖氨酸乙酰化，甲基化，泛素化和Sumoylafion以及高级培训工作为中心的各种驾驶生物学项目。包括在波多黎各的学生实习，与该提案的技术开发方面融为一体。技术和资源通过多种路线积极传播；静态和动态蛋白质组学数据集将被集中仓库/传播。