Pathophysiological mechanisms and treatment of red blood cell abnormalities

• Grant number: 19/18886-1
• Support Opportunities: Research Projects - Thematic Grants
• Start date: April 01, 2021
• End date: March 31, 2027
• 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 ; Paula de Melo Campos ; Renata Sesti Costa ; Sara Teresinha Olalla Saad ; Sarah Liane Linguet ; Stephan Menzel ; Susan Elisabeth Domingues Costa Jorge ; Wassim El Nemer ; Yves Colin
• Associated research grant(s): 24/02153-3 - Exploring the SLIT-ROBO Pathway in the Pathogenesis of Sickle Cell Retinopathy: In Vitro Analysis using ARPE-19 Retinal Cells and Patients Serum, AP.R; 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): 25/01351-9 - Retinal characterization in Townes mice model: Morphological parameters and gene expression of inflammatory and angiogenic markers, BP.IC; 24/17048-0 - Evaluation of Ineffective Erythropoiesis in Patients with Sickle Cell Anemia, BP.IC; 24/03283-8 - PROTEOMIC ANALYSIS IN SICKLE CELL RETINOPATHY IN RETINAS OF HUMANIZED HBSS-TOWNES MICE, BP.DR; + associated scholarships 24/15057-2 - Analysis of histopathology and molecular mechanisms involved in sickle cell retina-humanized HbSS-Townes mice., BP.TT; 24/10726-3 - The role of IL-1b and inflammasome activation in intravascular hemolysis-induced tissue iron accumulation, BP.PD; 24/07382-0 - New therapeutic strategies for sickle cell disease using CRISPR/Cas9 to produce hereditary persistence of non-deletional fetal hemoglobin Brazilian type (-195 C>G), "black" (-175 T>C) e greek (-117 G>A)., BP.PD; 24/06454-8 - Retrospective analysis of long-term toxicity of Hydroxyurea in patients with sickle cell anemia, BP.IC; 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; 23/11096-0 - CHARACTERIZATION OF THE RETINA IN A MOUSE MODEL TOWNES: MORPHOLOGICAL PARAMETERS AND MARKERS ANGIOGENIC, 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; 22/15058-3 - Protein and globin gene after the inhibition of Phosphatidylinositol-phosphate kinase-II-a (PIPKIIa), 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; 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

Abstract

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)

Scientific publications

(17)

(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)

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., 2022-10-01. (17/08122-9, 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., 2022-09-21. (14/00984-3, 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., 2023-07-01. (19/18886-1, 20/05985-9)

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., 2022-09-13. (17/08122-9, 19/17030-6, 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., 2022-04-01. (19/18886-1, 14/00984-3, 17/14594-0)

PEREIRA, DALILA ANDRADE; PEREIRA, DANILLO ANDRADE; SILVEIRA, TAMMYRIS HELENA REBECCHI; CALMASINI, FABIANO BERALDI; BURNETT, ARTHUR L.; COSTA, FERNANDO FERREIRA; SILVA, FABIO HENRIQUE. Heme-induced corpus cavernosum relaxation and its implications for priapism in sickle cell disease: a mechanistic insight. ANDROLOGY, v. 12, n. 8, p. 8-pg., 2024-01-17. (19/18886-1, 17/08122-9)

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., 2022-05-02. (08/57441-0, 13/07559-3, 14/00984-3, 15/13152-9, 19/18886-1, 08/10596-0, 12/06438-5)

COSTA, SUELI MATILDE DA SILVA; ITO, MIRTA TOMIE; DA CRUZ, PEDRO RODRIGUES SOUSA; DE SOUZA, BRUNO BATISTA; RIOS, VINICIUS MANDOLESI; DE HAIDAR E BERTOZZO, VICTOR; CAMARGO, ANA CAROLINA LIMA; VITURINO, MARINA GONCALVES MONTEIRO; LANARO, CAROLINA; DE ALBUQUERQUE, DULCINEIA MARTINS; et al. The molecular mechanism responsible for HbSC retinopathy may depend on the action of the angiogenesis-related genes ROBO1 and SLC38A5. Experimental Biology and Medicine, v. 249, p. 15-pg., 2024-07-24. (19/18886-1, 14/00984-3, 15/14255-6)

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., 2023-04-01. (19/09704-7, 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., 2023-04-03. (14/00984-3, 15/14255-6, 19/18886-1)

SILVEIRA, TAMMYRIS HELENA REBECCHI; PEREIRA, DALILA ANDRADE; CALMASINI, FABIANO BERALDI; COSTA, FERNANDO FERREIRA; BURNETT, ARTHUR L.; SILVA, FABIO HENRIQUE. Sympathetic hypoactivity leads to hypocontractility of the corpus cavernosum in sickle cell mice: a mechanism contributing to priapism. INTERNATIONAL JOURNAL OF IMPOTENCE RESEARCH, v. N/A, p. 6-pg., 2024-11-26. (19/18886-1, 17/08122-9)

LIMA CAMARGO, ANA CAROLINA; CARVALHO MONTE, ANA RAFAELA; DA SILVA COSTA, SUELI MATILDE; PEREIRA DE CASTRO, JULIA NICOLIELLO; LOPES DE FARIA, JACQUELINE MENDONCA; DATILO, MARCELLA NEVES; ROSA RODRIGUES, THIAGO ADALTON; COSTA, FERNANDO FERREIRA; MELO, MONICA B.. Retina transcriptomic landscape of HbSS Townes - a sickle cell disease mouse model. INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, v. 65, n. 7, p. 3-pg., 2024-06-01. (19/18886-1, 21/10159-3)

SILVA, FABIO H.; PEREIRA, DALILA A.; CALMASINI, FABIANO B.; COSTA, FERNANDO FERREIRA. Heme Reduces the Contraction of Corpus Cavernosum Smooth Muscle through the HO-CO-sGC-cGMP Pathway: Its Implications for Priapism in Sickle Cell Disease. Blood, v. 144, p. 1-pg., 2024-11-05. (19/18886-1, 17/08122-9)

SILVEIRA, TAMMYRIS HELENA REBECCHI; CALMASINI, FABIANO BERALDI; DE OLIVEIRA, MARIANA GONCALVES; COSTA, FERNANDO FERREIRA; SILVA, FABIO HENRIQUE. Targeting heme in sickle cell disease: new perspectives on priapism treatment. FRONTIERS IN PHYSIOLOGY, v. 15, p. 7-pg., 2024-07-17. (19/18886-1, 17/08122-9)

PEREIRA, DALILA ANDRADE; PEREIRA, DANILLO ANDRADE; PEREIRA, PAMELA DA SILVA; SILVEIRA, TAMMYRIS HELENA REBECCHI; CALMASINI, FABIANO BERALDI; REIS, LEONARDO OLIVEIRA; COSTA, FERNANDO FERREIRA; SILVA, FABIO HENRIQUE. Hydroxyurea does not reverse functional alterations of the nitric oxide-cGMP pathway associated with priapism phenotype in corpus cavernosum from sickle cell mouse. PLoS One, v. 18, n. 10, p. 11-pg., 2023-10-09. (19/18886-1, 17/08122-9)

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., 2022-01-12. (19/09704-7, 21/05191-5, 19/18886-1)

CONRAN, NICOLA; COSTA, FERNANDO F.. Sickle Cell Disease and Oxidative Stress: Implications for a Role of Diminished Endothelial SOD2 in Pulmonary Complications. FUNCTION, v. 3, n. 3, p. 2-pg., 2022-05-18. (20/06133-6, 19/18886-1)