IKK:Biophysical basis of dynamic regulation

IKK：动态调节的生物物理基础

基本信息

批准号：
8463406
负责人：
GOURISANKAR GHOSH
金额：
$ 50.65万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8463406
关键词：
Accounting Adverse effects Affect Analytical Centrifugation Architecture Arthritis Atherosclerosis Binding Binding Sites Biochemical Biochemical Reaction Biochemistry Biological Assay Biophysics Catalytic Domain Cell Line Cell Surface Receptors Cells Characteristics Chronic Chronic Disease Complex Computer Simulation Coupled Crystallography Development Disease Dissociation Dose Drug Targeting Effectiveness Enzymes Equation Estimation Techniques Family Feedback Genes Genetic Goals Half-Life Heat-Shock Proteins 90 Human Pathology IkappaB kinase Immune Immune response In Vitro Inflammatory Inflammatory Response Interleukin-1 Intervention Kinetics Lesion Libraries Malignant Epithelial Cell Malignant Neoplasms Maps Mass Spectrum Analysis Measures Mediating Methodology Modeling Molecular Molecular Chaperones Monitor Multienzyme Complexes NF-kappa B Natural regeneration Neoplasm Metastasis Nucleotides Outcome Pathogenesis Pathology Pathway interactions Peptide Hydrolases Pharmaceutical Preparations Pharmacological Treatment Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Phosphotransferases Physiological Physiology Play Protein Dephosphorylation Protein Kinase Protein Phosphatase 2A Regulatory Subunit PR53 Proteins Reaction Receptor Cell Receptor Down-Regulation Recycling Regulation Reporting Rest Role Scaffolding Protein Signal Transduction Signaling Protein Specificity Squamous cell carcinoma Stimulus Stream Structure Structure-Activity Relationship Study models TNF gene Testing Therapeutic Therapeutic Intervention Tumor Necrosis Factor Receptor Work autocrine base cancer cell cancer type cell type crosslink cytokine design high throughput screening immune activation in vivo inhibitor/antagonist mathematical model mutant novel paracrine reaction rate receptor reconstitution research study response self assembly simulation small molecule src-Family Kinases text searching transcription factor ubiquitin ligase upstream kinase

项目摘要

IKK is the major signaling hub for inflammatory and innate immune responses. It is an enzyme complex that receives signals from a large number of cellular receptors regulates that activity of the NF-kB family of transcription factors. Misregulation of IKK is associated with many chronic diseases, such as chronic inflammatory pathologies (arthritis, atherosclerosis, etc) and many different types of cancer. Genetic evidence strongly supports IKK's critical and central role in many functions in physiology and pathology, but its potential as a drug target has not been realized. Mechanistic and biophysical studies have been lacking, and we have neither a kinetic understanding of IKK regulation nor structural information. However, what is clear is that IKK mediates signaling specificity by tight dynamic control that is stimulus-specific and induces the expression of specific sets of genes. Recent studies have reported on a tightly coupled activation and inactivation mechanism that can only be described by a multi-state activation-inactivation cycle that involves the function of several enzymes with different functions, such as ubiquitin ligases, kinases, phosphatases, and foldases. Through regulation of these activities, we hypothesize that the IKK cycle is driven in a stimulus- and cell type-specific manner, and that understanding the kinetic relationships will reveal opportunities for rationally targeted pharmacological intervention that discriminate between disease associated misregulation and stimulus-responsive regulation in healthy cells. In this proposal, we will construct a mathematical model of the IKK cycle to explore the dynamic regulation of IKK activity. We will then focus biochemical and biophysical studies on specific control mechanisms. In particular, we test the roles of IKK oligomerization, conformational changes, and upstream kinases in IKK activation and inhibition of IKK. Computational simulations will guide genetic and pharmacological manipulation of IKK dynamics. Finally, we will focus our study on how TNF and IL-1 produce differential dynamic control of IKK; how differential dose response and temporal control determine the efficacy of cytokine traps.

IKK是炎症和先天免疫反应的主要信号枢纽。这是一种酶复合物来自大量细胞受体的信号调节NF-KB转录家族的活性因素。 IKK的正调与许多慢性疾病有关，例如慢性炎症病理学（关节炎，动脉粥样硬化等）和许多不同类型的癌症。遗传证据强烈支持IKK的关键在生理和病理学中许多功能中的核心作用，但其作为药物靶标的潜力并非实现。机械和生物物理研究一直缺乏，我们既不具有对 IKK监管或结构信息。但是，很明显，IKK通过紧密介导信号特异性刺激特异性的动态控制并诱导特定基因集的表达。最近的研究报道了只能由多状态描述的紧密耦合激活和灭活机制激活灭活周期涉及几种具有不同功能的酶的功能，例如泛素连接酶，激酶，磷酸酶和折叠酶。通过调节这些活动，我们假设IKK 循环以刺激和细胞类型特异性的方式驱动，并且理解动力学关系将揭示了理性靶向药理学干预的机会，以区分疾病健康细胞中相关的不调节和刺激反应性调节。在此提案中，我们将构建IKK周期的数学模型，以探索IKK的动态调节活动。然后，我们将将生化和生物物理研究集中在特定的控制机制上。特别是我们测试IKK寡聚，构象变化和上游激酶在IKK激活和抑制中的作用 ikk。计算模拟将指导IKK动力学的遗传和药理学操纵。最后，我们将把我们的研究集中在TNF和IL-1如何产生IKK的差异动态控制上；差异剂量反应如何时间控制决定了细胞因子陷阱的功效。