Structure-Function Studies of Chemokines and Receptors

趋化因子和受体的结构功能研究

基本信息

批准号：
7240578
负责人：
Tracy M Handel
金额：
$ 34.89万
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：
1994
资助国家：
美国
起止时间：
1994-12-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7240578
关键词：
Abbreviations Abnormal Cell Address Affinity Alzheimer&apos s Disease Animal Disease Models Area Asthma Atherosclerosis Binding Binding Proteins Biochemical Biochemistry CCL2 gene CXCL10 gene Carbohydrate Sequence Carbohydrates Cell physiology Cell surface Cells Chemokine, Other Chemotaxis Collaborations Complex Crystallization Defense Mechanisms Development Disease Disseminated Malignant Neoplasm Drug Industry Effectiveness Endopeptidases Engineering Environment Eotaxin Future G Protein-Coupled Receptor Genes G-Protein-Coupled Receptors Glycosaminoglycans Goals Grant HIV Heparin Heparitin Sulfate Homing Human Immune response Immune system Immunologic Surveillance Infiltration Inflammation Inflammatory Investigation Lead Ligands Lymphocyte Macrophage Inflammatory Proteins Medical Surveillance Methods Molecular Molecular Mimicry Multiple Sclerosis Mutagenesis Mutation Nomenclature Numbers Pathology Peptide Hydrolases Physiological Production Property Proteins Reagent Receptor Signaling Regulation Research Research Personnel Respiratory Burst Rheumatoid Arthritis Role Signal Pathway Signal Transduction Specificity Structural Models Structure Surveys System T-Cell Activation Terminology Testing Thermodynamics Variant Viral Virus Work analytical ultracentrifugation cell growth cell injury cell motility chemokine chemokine receptor cytokine design dimer human disease in vivo interest molecular modeling monocyte chemoattractant protein 1 receptor monomer pathogen preference programs protein function protein structure receptor receptor binding research study seven-transmembrane G-protein-coupled receptor structural biology therapeutic protein trafficking

项目摘要

DESCRIPTION (provided by applicant): The goal of the proposed research is to understand at a molecular level, how chemokines and their receptors control cellular migration and activation. These proteins are part of a surveillance system that protects the host from pathogens, abnormal cell growth, and other physiological insults. However, deregulated expression of chemokines or their receptors, and unabated infiltration and activation of cells, can cause cell damage. Thus many inflammatory diseases such as rheumatoid arthritis, asthma, multiple sclerosis and atherosclerosis are caused, at least in part, by chemokines. Chemokine receptors are also exploited by HIV as a means of cell entry. Furthermore, over the past few years it has been recognized that many other clinically important viruses mimic, exploit, or target chemokines and chemokine receptors as a mechanism for suppressing the host immune response. Chemokines and their receptors are therefore now considered attractive targets for the treatment of many human diseases. In order to understand how these proteins function, we take an approach that combines structural, biophysical, biochemical and in vivo studies. Specifically, our goals are to determine structures of these proteins, understand the molecular details of receptor binding and signaling, understand if, how, and why they bind to cell surface glycosaminoglycans (GAGs), and how viral chemokine proteins manipulate the chemokine system. In parallel with these fundamental studies we attempt to identify protein variants that are receptor antagonists, and therefore potential protein therapeutics or reagents that can be used to investigate the roles of specific receptors and chemokines in disease. The specific aims of the proposal are as follows: 1. Investigate the relevance and structural details of the interaction of chemokines with glycosaminoglycans, focusing on the chemokine MCP-1. 2. Identify specific GAG sequences that are preferentially recognized by chemokines. 3. Characterize the details of receptor binding, signaling and GAG binding of additional chemokines that bind to the MCP-1 receptor, CCR2. 4. Conduct a structural survey of chemokines that form higher order oligomers and/or that are oligomerized by GAGs to investigate the functional relevance of oligomerization and the diversity of oligomeric structures. 5. Characterize the interaction of chemokines with a viral chemokine binding protein.

描述（由申请人提供）：拟议研究的目的是在分子水平上了解趋化因子及其受体如何控制细胞迁移和激活。这些蛋白质是保护宿主免受病原体，异常细胞生长和其他生理损伤的监视系统的一部分。但是，趋化因子或其受体的失调表达以及细胞的浸润和激活不断会导致细胞损伤。因此，许多炎症性疾病，例如类风湿关节炎，哮喘，多发性硬化症和动脉粥样硬化，至少部分由趋化因子引起。趋化因子受体也被HIV剥削为细胞进入的手段。此外，在过去的几年中，人们已经认识到，许多其他重要的临床病毒模仿，剥削或靶向趋化因子和趋化因子受体是抑制宿主免疫反应的一种机制。因此，趋化因子及其受体现在被认为是治疗许多人类疾病的有吸引力的靶标。为了了解这些蛋白质的功能，我们采用一种结合结构，生物物理，生化和体内研究的方法。具体而言，我们的目标是确定这些蛋白质的结构，了解受体结合和信号传导的分子细节，了解它们是否，如何以及为什么与细胞表面糖胺聚糖（GAGS）结合，以及病毒趋化因子蛋白如何操纵趋化因子系统。与这些基本研究并行，我们试图鉴定受体拮抗剂的蛋白质变异，因此可以使用可用于研究特定受体和趋化因子在疾病中的作用的潜在蛋白质疗法或试剂。该提案的具体目的如下： 1。研究趋化因子与糖胺聚糖的相互作用的相关性和结构细节，重点是趋化因子MCP-1。 2。确定优先通过趋化因子识别的特定GAG序列。 3。表征与MCP-1受体CCR2结合的其他趋化因子的受体结合，信号传导和堵嘴结合的细节。 4.对趋化因子进行结构调查，形成高阶低聚物和/或被插入的寡聚，以研究寡聚化的功能相关性和寡聚结构的多样性。 5。表征趋化因子与病毒趋化因子结合蛋白的相互作用。