Regulation of immune reactions by synthetic thioglucans

合成硫葡聚糖对免疫反应的调节

• 批准号: 7708545
• 负责人: VACLAV VETVICKA
• 金额: $ 20.84万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7708545
• 关键词: Adjuvant Therapy; Adverse effects; Affect; Affinity; Bacteria; Binding; Biologic Characteristic; Biological; Biological Factors; Biological Response Modifiers; Cells; Charge; Chemical Structure; Clinical Trials; Complement Receptor; Complex Mixtures; Data; Disease; Drug or chemical Tissue Distribution; Evaluation; Experimental Models; Gene Expression; Genomics; Glucans; Goals; Host Defense; Human; Immune; Immune system; Immunocompetent; Immunomodulators; Infection; Japan; Lead; Leukocytes; Macrophage-1 Antigen; Malignant Neoplasms; Membrane; Microarray Analysis; Molecular Profiling; Molecular Weight; Mus; Natural Killer Cells; Oligonucleotides; Oligosaccharides; Oral; Pharmaceutical Preparations; Polymers; Probability; Property; Prophylactic treatment; Protozoa; Reaction; Recording of previous events; Regulation; Research; Signal Pathway; Solubility; Structure; Testing; Time; Viral; Yeasts; absorption; base; cancer therapy; clinical effect; clinical practice; crosslink; cytokine; dectin 1; design; improved; irradiation; macrophage; neutrophil; novel; pathogen; prevent; public health relevance; receptor; tumor

DESCRIPTION (provided by applicant): The major objective of this proposal is to develop, characterize and test new, synthetic version of a natural immunomodulator 2-glucan. Natural products useful in preventing and/or treating disease have been studied for a long time. Despite promising clinical trials and lack of understanding of their mechanism dampened enthusiasm. Natural glucans are large molecules with a low affinity for CR3 and have undesirable side effects because their large size enables them to cross-link CR3, stimulating a strong release of proinflammatory cytokines. Unfortunately, it has not been possible to generate small fragments of natural 2- glucan in a reproducible manner. The mechanisms of glucan actions were never fully established. The novel aims of our project involve: 1) synthesis of new, never before tested thioglucans; 2) comprehensive evaluation of cytokine stimulation; 3) the understanding of the absorption mechanisms leading to oral treatment for clinical practice; 4) evaluation of genomic. Aim #1 To design and synthesize new class of oligosaccharides. Main goal is to optimize chemical structures of oligo-2-(1,3)-glucans in order to improve stimulation of the immune system by: 1) increasing stability of oligoglucans, so that the probability of interactions between the immunostimulating agent and its receptor also increases; and 2) inducing better molecular interactions between glucans and their receptors present on immunocompetent cells. Aim #2 Determine the biological characteristics of small synthetic thioglucans. This goal will be achieved using four approaches: 1) evaluate their binding to the CR3 and Dectin-1 receptor; 2) determine their effects on induction of 13 different cytokines; 3) evaluation of the absorption and tissue distribution of orally administered glucans; and 4) comparing gene expression profiles between glucan-treated and untreated cells using microarray technology and evaluation of possible signaling pathways. Data from the proposed project will provide crucial understanding of the correlation between structure of quantitatively novel thioglucans and their effects on immune reactions, as well as important new information on the mechanisms by which glucans affect the cells. This project thus may lead to the new tumor therapy. PUBLIC HEALTH RELEVANCE: b-Glucan is a well-known biological response modifier that has been used as adjuvant therapy for cancer since 1980, mostly in Japan. b-Glucans also enhance innate host defense against certain bacteria, yeast, and viral pathogens. In addition, glucans are considered to be important prophylaxis against irradiation. In summary, b-glucan might be the most important natural immunomodulator. In this project, we propose to prepare improved synthetic oligosaccharides based on glucans and to characterize their biological properties. Based on our preliminary data, we hypothesize that these oligosaccharides will be more active and will overcome intrinsic problems with natural b-glucans that make them undesirable as drugs.

描述（由申请人提供）：本提案的主要目标是开发、表征和测试天然免疫调节剂2-葡聚糖的新合成版本。用于预防和/或治疗疾病的天然产品已经研究了很长时间。尽管有前景的临床试验和缺乏了解他们的机制挫伤了热情。天然葡聚糖是对CR 3具有低亲和力的大分子，并且具有不期望的副作用，因为它们的大尺寸使它们能够交联CR 3，刺激促炎细胞因子的强烈释放。不幸的是，不可能以可再现的方式产生天然β-葡聚糖的小片段。葡聚糖作用的机制从未完全确定。我们项目的新目标包括：1）合成新的，以前从未测试过的硫代葡聚糖; 2）全面评价细胞因子刺激; 3）理解导致临床实践口服治疗的吸收机制; 4）基因组评估。目的#1设计并合成一类新的寡糖。主要目标是优化寡-2-（1，3）-葡聚糖的化学结构，以通过以下方式改善对免疫系统的刺激：1）增加寡葡聚糖的稳定性，使得免疫刺激剂与其受体之间相互作用的可能性也增加;和2）诱导葡聚糖与免疫活性细胞上存在的其受体之间更好的分子相互作用。目的#2确定小合成硫代葡聚糖的生物学特性。这一目标将通过四种方法实现：1）评价它们与CR 3和Dectin-1受体的结合; 2）确定它们对13种不同细胞因子诱导的影响; 3）评价口服葡聚糖的吸收和组织分布; 4）使用微阵列技术比较葡聚糖处理和未处理细胞之间的基因表达谱，并评价可能的信号传导途径。来自拟议项目的数据将提供对定量新型硫代葡聚糖结构与其对免疫反应的影响之间的相关性的重要理解，以及关于葡聚糖影响细胞的机制的重要新信息。因此，该项目可能导致新的肿瘤治疗。公共卫生相关性：β-葡聚糖是一种众所周知的生物反应调节剂，自1980年以来一直被用作癌症的辅助治疗，主要在日本。β-葡聚糖还增强宿主对某些细菌、酵母和病毒病原体的先天防御。此外，葡聚糖被认为是重要的预防辐射。综上所述，β-葡聚糖可能是最重要的天然免疫调节剂。在这个项目中，我们建议制备基于葡聚糖的改进的合成寡糖并表征其生物学性质。根据我们的初步数据，我们假设这些寡糖将更有活性，并将克服天然b-葡聚糖的内在问题，使它们不受欢迎的药物。