项目来源

俄罗斯科学基金(RSF)

项目主持人

Sokolova Ekaterina

项目受资助机构

G.B.Elyakov Pacific Institute of Bioorganic Chemistry,Far Eastern Branch,Russian Academy of Sciences

立项年度

2020

立项时间

未公开

项目编号

20-74-00006

项目级别

国家级

研究期限

未知 / 未知

受资助金额

未知

学科

未公开

学科代码

未公开

基金类别

未公开

关键词

sulfated polysaccharides ; red algae ; innate immunity ; complement ; protein cascade system ; glycosaminoglycans

参与者

未公开

参与机构

未公开

项目标书摘要：nnotationComplement is a central part of innate immunity, which, as you know, serves as the first line of defense against foreign cells and altered host cells. At the moment, complement is undergoing a renaissance in modern immunology. The role of complement is not only the detection, labeling and elimination of microbial invasions with almost instant reactivity, but also with sufficient specificity to avoid damage to the host cells. Both ineffective and excessive complement stimulation are associated with increased susceptibility to infectious or non-infectious diseases, including autoimmune disorders, chronic inflammation, thrombotic microangiopathy, transplant rejection and oncology. It is worth noting that, as a result of the recently proved noncanonical activation of complement by coagulation / fibrinolytic cascade enzymes, anaphylotoxins are the main product of enzymatic catalysis. Anaphylotoxins mediate chemotaxis, inflammation and the formation of cytotoxic oxygen radicals, also cause smooth muscle contraction, the release of histamine from mast cells and increased vascular permeability. The listed properties of these molecules thus have a pronounced pro-inflammatory effect and, therefore, are the target of many anti-inflammatory drugs. A number of complement regulators, such as factor H and properdine, interact with carbohydrate molecules, primarily glycosaminoglycans and sialic acid, on the membranes of the host and pathogen cells and direct the corresponding complement response by stimulating the binding of complement activators or inhibitors. Sulfated polysaccharides are one of the promising candidates for imitating the structure of glycosaminoglycans, and hence regulating complement.The proposed project, therefore, is aimed at solving the problem of modulating the immune system of the human body using natural sulfated polysaccharides from red algae. The main goal of the project is to reveal the glycoaminoglycan-mimicking properties of sulfated polysaccharides on the complement protein cascade system. To better understand the role of sulfated galactans in the complement system, the contribution of proteins from other protein cascades, for example, fibrinolytic, will also be taken into account in order to establish the mechanism of action and expand the potential spectrum of application of algae polysaccharides with respect to anaphylotoxins.The scientific novelty of the project is determined by the choice of substances and biochemical studies necessary to develop and evaluate the effectiveness of new tools for regulating and / or inhibiting both the activity of the canonical pathways of complement activation and a more in-depth action. The latter will be oriented to proteins of other non-complement cascades whose complement activating action was recognized only in 2010. The innovativeness of the proposed approaches and methods for the study of complement activity in the presence of sulfated polysaccharides of red algae consists in using not hemolysis models, but experiments conducted on the surface of microplates coated with specific activators that act selectively and with a high level of sensitivity. In addition, an experiment will be conducted for the first time on the involvement of proteases of an incomplete cascade (coagulation / fibrinolytic), as well as regulatory factors of the complement system. The knowledge gained as a result of the project will open up the prospect of a new use of biopolymers with a unique structure, due to the marine origin and habitat of algae, for the prevention and development of inflammatory reactions of the body, which are based on incorrect functioning of the complement system.
        The complement system is an effective first line of defense against the invasion of pathogenic microorganisms, the violation of the delicate balance of which in its activating or controlling proteins is increasingly associated with the pathology of diseases. The results expected from the implementation of this project will show the possible prospects of using polysaccharides of natural origin for the correction of complement disorders by simulating the properties of glycosaminoglycans of cell membranes. Since the proteins of the complement system are synthesized in all human organs and tissues, the spectrum of the possible use of the studied substances includes ophthalmology, dermatology and the work of the gastrointestinal tract. For all three of the above areas, algae polysaccharides are allowed and used by humans, thereby revealing the potential use of these substances in medical practice.At the moment, the world literature contains only partial information about the ability of these substances to modulate complement and they are performed on non-modern hemolysis models, not to mention the complete lack of data on their effect on regulatory factors of complement. The depth and versatility of the proposed project (for example, canonical and non-canonical activation paths) will allow a comprehensive study of the ability of sulfated polysaccharides to modulate a variety of complement links (complement activation and, conversely, regulation, H / D factor).
        Annotation of the results obtained in 2020The research described here presents data on the effect of galactans of red algae, carrageenans (λ/μ/ν-, κ-, κ/β-, and ι/κ-types), and agar on complement system activation in normal human serum. The experiments were based on well surfaces coated with triggering agents for binding initiating complement components —C3 and C4. The sulfated galactans inhibited C3 binding to lipopolysaccharide with direct dependence on the sulfation degree of polysaccharides. Sulfation degree was also important in carrageenans’ capacity to reduce C4 binding to mannan. However, C4 binding to antibodies was considerably activated by carrageenans, especially with 3,6-anhydrogalactose. The gelling carrageenans were able to block antigen binding centers of total serum IgM and with more intensity than non-gelling. No structural characteristics mattered in ameliorating C5 cleavage by plasmin in extrinsic protease complement activation, but λ/μ/ν- and κ/β-carrageenans almost completely inhibited C5 cleavage. Thus, galactans participated in cell surface biology by imitating surface glycans in inhibition of C3 binding and mannose binding lectin, but as to the classical pathway these substances stimulated complement, probably due to their structure based on carrabiose.List of publications:https://doi.org/10.47471/17_2020_09_07_10_23https://www.sciencedirect.com/science/article/abs/pii/S0144861720314247?casa_token=7YUmWcatVUYAAAAA:QhCNCqM4qE3bJdzU8409XSn-BCsyWWTltcaDegzISmRcoB5GzovIUATbDTHqD7lqGXtE2b7G1TU