Molecular Biology of Lymphocyte and Neuronal Growth

淋巴细胞和神经元生长的分子生物学

• 批准号: 7210633
• 负责人: DAVID BALTIMORE
• 金额: $ 50.29万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-12-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7210633
• 关键词: A20 protein; Address; Autoimmune Diseases; Baltimore; Behavior; Binding; Binding Sites; Biochemical; Biological; C-terminal; Cell Line; Computer Simulation; DNA Binding; Family; Family member; Feedback; Fibrinogen; Gene Activation; Gene Expression; Genes; Genetic Transcription; Genome; Genomics; Goals; Heart Diseases; Immune response; Industry; Inflammatory; KB Cells; Knockout Mice; Knowledge; Lymphocyte; Malignant Neoplasms; Medical; Methods; Modeling; Molecular; Molecular Biology; Molecular Mechanisms of Action; NF-kappa B; Nucleotides; Numbers; Paper; Pathologic; Pathway interactions; Physiological; Play; Post-Translational Protein Processing; Proteins; Proteomics; RNA Interference; Regulation; Reporting; Repression; Research Personnel; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Specific qualifier value; Specificity; Stimulus; System; TNF gene; Techniques; Testing; Time; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Ubiquitin; Ubiquitination; Work; Yeasts; cell type; fascinate; follow-up; human TNF protein; inhibitor/antagonist; interest; knockout gene; neglect; neuronal growth; programs; promoter; response; tool; transcription factor; yeast two hybrid system

DESCRIPTION (provided by applicant) Since we discovered the NF-kappaB transcription factor in 1986, it has emerged as a key activator of inflammatory and immune responses with important pathologic roles in cancer, heart disease and autoimmune diseases. For these reasons, understanding the details of the control of NF-kappaB and of its transcriptional capabilities has great medical as well as biological significance. In the proposed work, we will take four approaches to deepening our understanding of NF-kappaB. First, we will further investigate the roles of the various forms of the DNA binding site for NF-kappaB, the kappaB site. We have recently observed that particular kappaB sites are highly conserved over evolutionary time, implying that each contains information within every one of its nucleotides, a conclusion that was very surprising given the wide variety of sites that exist in the genome. We propose various approaches to understanding what information is encoded by the various kappaB sites. Our second goal is to use modeling tools combined with experimental tests to better understand the pathways that control NF-kappaB activation and repression. The third approach is to concentrate study on one protein, A20, which is known to play a role in limiting NF-kappaB activation. The turning off of NF-kappaB is as important as its activation, because it of its enormous pathologic potential, and A20 is an important protein in this regard. We have a clue that A20 might be involved in inhibiting a key protein modification that is important for NF-kappaB activation and we will follow that up in many directions. The fourth approach is to study an activator of NF-kappaB that has thus far been neglected, the B94 protein. Here we have made only minimal progress thus far but we outline a variety of methods of attack using genomic and proteomic tools.

自1986年我们发现NF-kappaB转录因子以来，它已成为炎症和免疫反应的关键激活因子，在癌症、心脏病和自身免疫性疾病中具有重要的病理作用。由于这些原因，了解NF-kappaB的控制及其转录能力的细节具有重要的医学和生物学意义。在拟议的工作中，我们将采取四种方法来加深我们对NF-kappaB的理解。首先，我们将进一步研究NF-kappaB的各种形式的DNA结合位点的作用。我们最近观察到，特定的kappaB位点在进化过程中是高度保守的，这意味着每个位点都包含每个核苷酸中的信息，考虑到基因组中存在的位点的多样性，这一结论非常令人惊讶。我们提出了各种方法来理解由各种kappaB编码的信息