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Effect of passive immunization with nanoparticles derivatized with fragments of a single chain variable anti-electronegative LDL in the development of atherosclerosis in mice knockout for the gene of the LDL receptor.

Grant number: 10/02918-7
Support type:Scholarships in Brazil - Master
Effective date (Start): August 01, 2010
Effective date (End): February 29, 2012
Field of knowledge:Health Sciences - Pharmacy
Principal researcher:Dulcineia Saes Parra Abdalla
Grantee:Marcela Frota Cavalcante
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Heart diseases are among the major causes of morbidity and mortality worldwide and atherosclerosis is at the top of these diseases, accounting for more fatalities than all cancers combined. Atherosclerosis is a chronic inflammatory multifactorial disease with involvement of the immune system, with innate and adaptive immunity´s participation and being the result of different cellular elements´ interaction such as lymphocytes, macrophages, endothelial cells and smooth muscle cells. The electronegative LDL, a modified fraction of native LDL, plays a key role in atherosclerosis, since the changes undergone by the molecule are able to induce the accumulation of cholesterol esters in macrophages and the subsequent formation of foam cells. Having confirmed the involvement of the immune system in the atherogenic process, it is necessary to handle its action through the use of alternatives such as: the use of immunosuppressive drugs or the execution of an immunization, whether passive or active. Recombinant antibodies have been generated in recent decades, through antibodies´ genetic engineering techniques. Currently, besides the use of monoclonal antibodies (proteins produced from mice or rats and used in humans), which use is limited for their significant immunotoxicity, have also been generated humanized antibodies such as F (ab ') 2 fragments and active antibodies´ fragments, such as scFv, which can be generated in bacteria such as Escherichia coli and yeasts such as Pichia pastoris. The scFv is the smallest functional unit of the antibody and is believed to be used as a new alternative treatment for the development of atherosclerosis or as a preventive factor for the lesion´s appearance. In order to increase the efficiency of scFv´s action in the body, nanoparticles have been developed and combined with these fragments, since there is great probability that the system has low immunogenicity, apropriate half-life in circulation, control of the molecular recognition of antigen and of the immune complexes´ removal by the immune system. Given the role of LDL (-) in atherosclerosis, this project aims to evaluate the treatment effect of anti-LDL (-) scFv fragments and of anti-LDL (-) scFv fragments conjugated to nanoparticles, previously synthesized, in passive immunization of knockout mice for LDL receptor (-/-), regarding the development and progression of atherosclerosis.

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