Structure-Function Studies of Chemokines and Receptors

趋化因子和受体的结构功能研究

• 批准号: 8100650
• 负责人: Tracy M Handel
• 金额: $ 17.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100650
• 关键词: Abbreviations; Abnormal Cell; Address; Affinity; Alzheimer' 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; Chemotaxis; Collaborations; Complex; Crystallization; Defense Mechanisms; Development; Disease; Disseminated Malignant Neoplasm; Drug Industry; Effectiveness; 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; Methods; Molecular; Molecular Mimicry; Molecular Models; Multiple Sclerosis; Mutagenesis; Mutation; Nomenclature; 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 complex; protein function; protein structure; receptor; receptor binding; research study; seven-transmembrane G-protein-coupled receptor; structural biology; therapeutic protein; trafficking

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）：拟议研究的目标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。然而，趋化因子或其受体的表达失调以及细胞的浸润和激活有增无减，可能会导致细胞损伤。因此，许多炎性疾病例如类风湿性关节炎、哮喘、多发性硬化症和动脉粥样硬化至少部分是由趋化因子引起的。 HIV 也利用趋化因子受体作为进入细胞的手段。此外，在过去几年中，人们已经认识到许多其他临床上重要的病毒模仿、利用或靶向趋化因子和趋化因子受体作为抑制宿主免疫反应的机制。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，我们采取了结合结构、生物物理、生物化学和体内研究的方法。具体来说，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、如何以及为何与细胞表面糖胺聚糖 (GAG) 结合，以及病毒趋化因子蛋白如何操纵趋化因子系统。在进行这些基础研究的同时，我们试图鉴定作为受体拮抗剂的蛋白质变体，从而找到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治疗剂或试剂。该提案的具体目标如下： 1. 研究趋化因子与糖胺聚糖相互作用的相关性和结构细节，重点关注趋化因子 MCP-1。 2. 识别趋化因子优先识别的特定 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 GAG 结合的细节。 4. 对形成更高阶寡聚体和/或由 GAG 寡聚化的趋化因子进行结构调查，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。