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| Author(s): |
Carolina Carvalho Dias
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) |
| Defense date: | 2019-05-15 |
| Examining board members: |
Ricardo Ambrosio Fock;
Fernando Salvador Moreno;
Camila Aparecida Machado de Oliveira;
Helena Regina Comodo Segreto
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| Advisor: | Ricardo Ambrosio Fock; Edgar Julian Paredes Gamero |
| Abstract | |
Malnutrition is a nutritional disorder characterized by inadequate intake of food or nutrients. Previous studies in our group have demonstrated that protein malnutrition causes hematological changes such as anemia and leukopenia, as well as quantitative and structural changes in the medullary microenvironment. Among the several molecules that have action in the metabolic and energetic regulation of the organism and also in hematopoiesis, leptin has emerged as a strong candidate. Thus, studies related to synthetic fragments of leptin have been of great importance because they have a low cost and are easier to produce. A previous study with modified synthetic leptin fragment, demonstrated its bioactivity by modulating hematopoietic stem cell proliferation. Knowing that the hematopoietic system of the animal model of protein malnutrition is extensively compromised, we studied the modulatory effects of this fragment (LEP5) on hematopoiesis. The results demonstrate that the synthetic fragment LEP5, in protein malnutrition animal models, is able to: (I) Positively modulate the hematopoietic system of malnourished animals (confirmed by analysis cell cycle, medullar cytotoxicity and hemogram), clonogenic capacity (increasing the amount of GM-CFU); although, it was not possible to observe modulations in splenic cells. (II) The biochemical test revealed no alteration of the parameters evaluated in this animal model, when compared to the group of malnourished animals. (III) Quantification of the cytokines currents and medullary supernatant were not altered. (IV) The p-JAK2 protein (main leptin signaling pathway) was activated. (V) Histopathological analysis confirms results found from the positive modulation observed by the fragment in the model of protein malnutrition. However, the kidney, spleen and liver histopathological analysis, denote an acute inflammatory condition by the treatment. (VI) The hematological profile confirms the results obtained by hemogram and anemia recovery. Immunophenotypic analysis of thymus and peripheral blood reveals positive induction by treatment. In addition, cell cycle analysis and cell viability in hematopoietic stem cells confirm positive modulation results observed in the bone marrow. There was also an increase in the expression of LEPR+, in HSC, of the malnourished models treated, with LEP5 and increase intracellular Ca2+. (VII) Finally, after mass spectrometric analysis, the peptide does not degrade rapidly in bovine serum which demonstrates stability of the fragment, as the treatment does not lead to oxidative stress. Thus, the therapeutic potential of the LEP5 fragment has been demonstrated. (AU) | |
| FAPESP's process: | 15/04438-6 - Assessment of modulatory effects and mechanisms of the synthetic fragment of leptin LEP5 in the regulation of hematopoiesis of mice subjected to protein malnutrition |
| Grantee: | Carolina Carvalho Dias |
| Support Opportunities: | Scholarships in Brazil - Doctorate |