Regulation of immune reactions by synthetic thioglucans

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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.