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Pathophysiological mechanisms and treatment of red blood cell abnormalities

Grant number: 19/18886-1
Support Opportunities:Research Projects - Thematic Grants
Duration: April 01, 2021 - March 31, 2026
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Fernando Ferreira Costa
Grantee:Fernando Ferreira Costa
Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Pesquisadores principais:
Mônica Barbosa de Melo ; Nicola Amanda Conran Zorzetto
Associated researchers: Berengere Koehl ; Carla Fernanda Franco Penteado ; Carolina Lanaro ; Caroline Le Van Kim ; Darío Ariel Estrin ; Dulcinéia Martins de Albuquerque ; Erich Vinicius de Paula ; Fábio Henrique da Silva ; Flávia Costa Leonardo ; Jacqueline Mendonça Lopes de Faria ; Jean Leandro dos Santos ; Kleber Yotsumoto Fertrin ; Magnun Nueldo Nunes dos Santos ; Marcos André Cavalcanti Bezerra ; Marcus Alexandre Finzi Corat ; Maria de Fatima Sonati ; Mickaël Marin ; Renata Sesti Costa ; Stephan Menzel ; Susan Elisabeth Domingues Costa Jorge ; Wassim El Nemer ; Yves Colin
Associated grant(s):23/01379-5 - Evaluation of the microbiome and intestinal permeability of mice with Sickle Cell Anemia and the relationship with inflammatory processes and the effects of treatment with hydroxyurea and probiotics, AP.R
22/11687-6 - Multi-user equipment approved in grant 19/18886-1: PeriCam PSI NR, AP.EMU
Associated scholarship(s):23/08178-5 - The role of podoplanin and CLEC-2 pathway in the sickle cell disease, BP.DR
23/09206-2 - Effect of heme on the expression of inflammatory mediators in HMEC-1 cells, BP.IC
23/05315-1 - Gene Expression and Protein Profiling of Phosphatidyl-Inositol-phosphate-kinases (PIPKins) in Adults and Neonates, BP.IC
23/05314-5 - Supplementation of Stored Red Blood Cells for Transfusion Purposes: Studies of Cell Viability and Biochemical Parameters, BP.IC
23/06342-2 - Synthesis of new iron chelators and pharmacological evaluation in an animal model of iron overload associated with Sickle Cell Anemia, BP.PD
23/05188-0 - Function of Hemoglobin in individuals with Secondary Erythrocytosis, BP.IC
23/00108-8 - Finding Potential Compounds to Improve Functional Efficiency of Hemoglobin in Red Blood Cells Concentrate (Blood Bags): a Prospective Study, BP.IC
22/15313-3 - Screening of Compounds to Increase Hemoglobin- Oxygen Affinity for Therapeutic Purposes, BP.IC
23/01293-3 - New selective HDAC Inhibitors class I and PROTACs: evaluation of the ability to induce gamma globin in vivo and in vitro, BP.DD
22/15058-3 - Protein and globin gene after the inhibition of Phosphatidylinositol-phosphate kinase-II-a (PIPKIIa), BP.IC
21/14089-0 - Evaluation of gene expression profile of endothelial progenitor cells of patients with sickle cell anemia and stroke, BP.MS
22/00429-6 - Identification of polymorphisms related to fetal hemoglobin increase and association with HbF values and variability of F cell distribution, BP.IC
21/14299-4 - New therapeutic strategies for sickle-cell disease using CRISPR/Cas9 to produce hereditary persistence of non-deletional fetal hemoglobin of the types: Brazilian (-195 C>G), "black" (-175 T>C) and Greek (-117 G>A), BP.PD
21/11851-8 - Defining vaso-occlusion and approaches for its reversal, BP.PD
21/10159-3 - Identification of proteins involved in Sickle Cell Retinopathy in retinas of humanized mice HbSS-Townes, BP.PD - associated scholarships


The proposed Thematic Project "Pathophysiological Mechanisms and Treatment of Red Blood Cell Abnormalities" will be developed by the Red Blood Cell Research Group at the Hematology Center, the Department of Clinical Pathology and the Center for Molecular Biology and Genetic Engineering (CBMEG), UNICAMP, in collaboration with various Brazilian and international researchers. The project aims to expand and implement new therapeutic approaches in red blood cell diseases, elucidate mechanisms of these diseases with potential for the development of treatments and continue our structural and functional analyzes of variant hemoglobins. We present a consistent set of well-focused investigations: The identification of as yet elucidated pathophysiological mechanisms responsible for the major red cell diseases and the testing of innovative therapeutic strategies that may contribute significantly to the cure of these diseases. The proposal is based on results obtained in recent years by the group of researchers involved and on the major methodological advances that have occurred in this area, with special emphasis on the use of new gene editing techniques, modern methods for studying gene expression, imaging cytometry, the use of animal models of diseases and the use of in vitro mechanisms for the study of cellular function. The infrastructure available is remarkable; we can highlight: Cytometry equipment, such as the Amnis Image Stream, for visualization of interactions and morphological characteristics of cells, and the CytoFlex for detection of microvesicles; the Cellix Venaflux microfluidic equipment for in vitro erythrocyte studies; and ECIS for monitoring the endothelial cell barrier. Our strategy is to identify three major areas of study related to red cell diseases that include a total of 14 subprojects. The first area concerns investigations related to the functional study of abnormal hemoglobins. The second area of study comprises subprojects that relate to various aspects of the pathophysiological mechanisms of red blood cell disease. Important findings previously obtained in this field of investigation may be translated into therapeutic options. Among the subprojects included in this area are studies of the association of macrophages and monocytes with erythropoiesis and iron metabolism; and the use of animal models of sickle cell disease to analyze cellular functions, new models of clinical changes such as retinopathy and the production of an animal with sickle cell disease associated with PHHF. The third area of study encopasses projects related to the treatment of red blood cell diseases, including strategies to increase fetal hemoglobin (HbF) production, identification of genes related to this event, and the evaluation of the efficacy of this increase in HbF in patients treated with hydroxyurea; projects that aim to development approaches to reduce the deleterious effects of hemolysis; projects aimed at preventing or reversing the effects of vascular occlusion and the analysis of new molecules with iron-chelating properties. The goal of this area is to investigate new therapeutic possibilities, in particular, the use of CRISPR-Cas9 gene editing to induce HbF production; in this case, our preliminary results are highly promising. (AU)

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Scientific publications (10)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SESTI-COSTA, RENATA; SILVA-FILHO, JOAO LUIZ; BARCELLINI, WILMA; LE VAN KIM, CAROLINE; CONRAN, NICOLA. Editorial: Inflammatory Mechanisms of Hemolytic Diseases. FRONTIERS IN IMMUNOLOGY, v. 12, p. 3-pg., . (19/09704-7, 21/05191-5, 19/18886-1)
BERTOZZO, VICTOR DE HAIDAR E.; COSTA, SUELI MATILDE DA SILVA; ITO, MIRTA TOMIE; DA CRUZ, PEDRO RODRIGUES SOUSA; SOUZA, BRUNO BATISTA; RIOS, VINICIUS MANDOLESI; VITURINO, MARINA GONCALVES MONTEIRO; DE CASTRO, JULIA NICOLIELLO PEREIRA; RODRIGUES, THIAGO ADALTON ROSA; LANARO, CAROLINA; et al. Comparative transcriptome analysis of endothelial progenitor cells of HbSS patients with and without proliferative retinopathy. Experimental Biology and Medicine, v. 248, n. 8, p. 8-pg., . (14/00984-3, 15/14255-6, 19/18886-1)
SESTI-COSTA, RENATA; COSTA, FERNANDO F. F.; CONRAN, NICOLA. Role of Macrophages in Sickle Cell Disease Erythrophagocytosis and Erythropoiesis. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 24, n. 7, p. 15-pg., . (19/09704-7, 19/18886-1)
GIL, GISLENE PEREIRA; ANANINA, GALINA; MASCHIETTO, MARIANA; LIMA, SHEILA COELHO SOARES; DA SILVA COSTA, SUELI MATILDE; BAPTISTA, LETICIA DE CARVALHO; ITO, MIRTA TOMIE; COSTA, FERNANDO FERREIRA; COSTA, MARIA LAURA; DE MELO, MONICA BARBOSA. Epigenetic analysis in placentas from sickle cell disease patients reveals a hypermethylation profile. PLoS One, v. 17, n. 9, p. 23-pg., . (14/00984-3, 19/18886-1)
TORRES, LIDIANE S.; CHWEIH, HANAN; FABRIS, FERNANDA C. Z.; GOTARDO, ERICA M. F.; LEONARDO, FLAVIA C.; OLALLA SAAD, SARA T.; COSTA, FERNANDO F.; CONRAN, NICOLA. TGF-beta 1 Reduces Neutrophil Adhesion and Prevents Acute Vaso-Occlusive Processes in Sickle Cell Disease Mice. CELLS, v. 11, n. 7, p. 12-pg., . (19/18886-1, 14/00984-3, 17/14594-0)
SOUSA DA CRUZ, PEDRO RODRIGUES; ANANINA, GALINA; SECOLIN, RODRIGO; GIL-DA-SILVA-LOPES, VERA LUCIA; PASSOS LIMA, CARMEN SILVIA; CONDEIXA DE FRANCA, PAULO HENRIQUE; DONATTI, AMANDA; LOURENCO, GUSTAVO JACOB; DE ARAUJO, TANIA KAWASAKI; SIMIONI, MILENA; et al. Demographic history differences between Hispanics and Brazilians imprint haplotype features. G3-GENES, GENOMES, GENETICS, v. N/A, p. 13-pg., . (08/57441-0, 13/07559-3, 14/00984-3, 15/13152-9, 19/18886-1, 08/10596-0, 12/06438-5)
PEREIRA, PAMELA DA SILVA; PEREIRA, DALILA ANDRADE; CALMASINI, FABIANO BERALDI; REIS, LEONARDO O.; BRINKMAN, NATHAN; BURNETT, ARTHUR L.; COSTA, FERNANDO FERREIRA; SILVA, FABIO HENRIQUE. Haptoglobin treatment contributes to regulating nitric oxide signal and reduces oxidative stress in the penis: A preventive treatment for priapism in sickle cell disease. FRONTIERS IN PHYSIOLOGY, v. 13, p. 12-pg., . (17/08122-9, 19/17030-6, 19/18886-1)
DE PAULA, ERICH VINICIUS; MARTINS, MARCIO SOUZA; BORTOLUZO DE LORENZO, ANA LUISA; LINO DUARTE, BRUNO KOSA; REZENDE, SUELY MEIRELES; COSTA, FERNANDO FERREIRA. The landscape of hematology research in Brazil: an analysis of data from citation databases. Hematology, Transfusion and Cell Therapy, v. 45, p. 11-pg., . (19/18886-1, 20/05985-9)
MAGRINI IACOPUCCI, ANA PAULA; PEREIRA, PAMELA DA SILVA; PEREIRA, DALILA ANDRADE; CALMASINI, FABIANO BERALDI; PITTALA, VALERIA; REIS, LEONARDO OLIVEIRA; BURNETT, ARTHUR L.; COSTA, FERNANDO FERREIRA; SILVA, FABIO HENRIQUE. Intravascular hemolysis leads to exaggerated corpus cavernosum relaxation: Implication for priapism in sickle cell disease. FASEB JOURNAL, v. 36, n. 10, p. 9-pg., . (17/08122-9, 19/18886-1)

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