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VALIDATION AND INHIBITION EVALUATION OF DIFFERENT EXPRESSED PROTEINS OF PLATELETS FROM DEEP VENOUS THROMBOSIS PATIENTS

Grant number: 12/04040-4
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): November 01, 2012
Effective date (End): February 29, 2016
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Joyce Maria Annichino-Bizzacchi
Grantee:Mariane Cristina Flores Nascimento
Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Deep venous thrombosis (DVT) is multi-causal disease associated to a high morbi-mortality due to complications as pulmonary embolism and post-flebitic syndrome, and about 25 % of the patients will present recurrence in 5 years. The identification of new factors involved to the physiopathology of the DVT is important in clinical practice. We previously analyzed the platelets proteins by proteomics and identified 5 proteins only on samples from 3 chronic and spontaneous DVT patients. These proteins were absents in all the healthy controls included, which were a sibling and a neighbor for each patient included. The platelet proteins were the Apolipoprotein A1 Binding-Protein (APOA1BP), ¶1 sub-unit of Coatomer (COPZ1), Estradiol 11-17-² Dehydrogenase (11-17ED), Leukotriene A-4 Hydrolase (LA4H) and Sorbitol Dehydrogenase (SORD). Our hypothesis is that the APOA1BP would be a protective protein, expressed in an attempt to minimize the damage, and the other four proteins would have a deleterious action, and would play a role on metabolism, inflammation and lipids transport. In order to validate these data, the Real Time-PCR analysis will be performed on RNA obtained from platelets of patients and controls on target genes amplification using the 2(-DeltaDeltaCT) values to normalize the data. After that, in order to explore the in vivo influence of APOA1BP and COPZ1 on physiopathology of DVT, specific recombinant lentiviral vectors for RNA interference targeting to Rattus norvegicus will be designed and the best knock downs will be selected by real-time PCR. The influence of the inhibition of these proteins will be evaluated by the stasis of vena cava from rats mediated by FeCl3, and the size, weight and morphology of the thrombus will be analyzed. The same model will be applied by the evaluation of inhibition of LA4H, 11-17ED and SORD by bestatin, bis(hydroxyphenyl) azoles and fidarestat respectively, three potent inhibitors of their proteins or their precursors. Each medication will be administrated to six animals for seven days before the DVT induction, which will be compared to other six animals infused with PBS.

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