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Inflammation markers and kallikrein-kinin system in mucopolysaccharidosis type I model

Grant number: 18/25921-5
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): June 01, 2019
Effective date (End): May 31, 2020
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:João Bosco Pesquero
Grantee:Gabriel Compri Nardy
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Mucopolysaccharidosis type I (MPSI) is an inborn error of metabolism of autosomal inheritance, with progressive character, due to the deficiency of the alpha-L-iduronidase enzyme, responsible for the degradation of glycosaminoglycans (GAGs) dermatam sulfate and heparam sulfate, leading to these substances storage in lysosomal. Lysosomal storage leads to various cellular and tissue dysfunctions. Individuals with MPSI may present several clinical conditions that allow classification of the disease into two main subtypes: Hurler syndrome (severe), with severe neurological, respiratory, cardiovascular and joint problems; and Scheie and Hurler-Scheie syndrome (attenuated), with minimal or absent neurological dysfunctions and multisystemic somatic disorders that reduce life expectancy. In inborn errors of metabolism, disorders resulting from mutations of genes encoding enzymes come directly from enzyme deficiency and indirectly from the inflammation promoted in the various tissues. To treat these diseases, it is possible to use drugs that reduce inflammation and thus reduce symptoms, such as with hereditary angioedema. However, the inflammatory process related to the MPSI symptomatology has not yet been well understood, which restricts the treatment of the disease only to enzymatic deficiency without a possible involvement of the inflammatory component. In this study to be performed with knockout animals for the alpha-L-iduronidase enzyme gene, the MPSI symptomatology, the inflammatory process and its markers will be analyzed, with emphasis on the B1 receptor of the kallikrein-kinin system, which will subsequently be targeted pharmacological treatment with antagonist. It is expected that at the end of this work a possible new co-treatment for MPSI based on the pharmacological use of antagonists for the B1 kinin receptor.