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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.

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