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Immune signature in telomeropathies

Grant number: 19/17520-3
Support type:Regular Research Grants
Duration: January 01, 2020 - December 31, 2022
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Cooperation agreement: King's College London
Principal researcher:Rodrigo do Tocantins Calado de Saloma Rodrigues
Grantee:Rodrigo do Tocantins Calado de Saloma Rodrigues
Principal researcher abroad: Judith Christine Watson MARSH
Institution abroad: King's College London, England
Home Institution: Hemocentro de Ribeirão Preto. Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da USP (HCMRP). Secretaria da Saúde (São Paulo - Estado). Ribeirão Preto , SP, Brazil
Assoc. researchers: Diego Villa Clé ; Flávia Sacilotto Donaires Ramos ; Luiz Fernando Bazzo Catto ; Willian Robert Gomes


Telomeres are the repetitive nucleotide structures at the end of the linear chromosomes that, when critically short, engage cell senescence, apoptosis, or chromosome instability. In cells with high proliferative demand, telomeres are repaired by telomerase, a reverse transcriptase that adds hexanucleotides to the 3' end of the DNA leading strand. In humans, germline mutations in telomere-biology genes may cause disorders (telomeropathies) associated with defective cell regeneration and may affect the bone marrow, skin, lungs, and liver, and a proclivity for cancer development. In the haematopoietic compartment, abnormal telomere erosion provokes an exhaustion of the haematopoietic stem cell pool, resulting in a hypocellular bone marrow and pancytopenia, which may be clinically diagnosed as aplastic anaemia. Telomere dysfunction also may trigger failure of other organs, such as the lungs, causing pulmonary fibrosis, and the liver, causing cirrhosis. Particularly characteristic of the lungs and liver is the profibrotic damage to the organs. Recent studies have compelling evidence that the immune system contributes to disease phenotype. Our preliminary findings suggest a Th1-biased profile in the liver of telomerase-deficient mice when challenged by S. mansoni infection. Their hepatocytes are metabolic dysfunctional and more likely to trigger chronic injury/repair. Additionally, it has been demonstrated in humans that short telomeres cause primary T cell immunodeficiency and activate distinct molecular pathways of T cell apoptosis with aging. In this collaborative study between the University of São Paulo (USP) and the King's College Hospital (KCH), we plan to join the cohorts of patients with telomeropathies from both institutions and immunologically characterize those patients with bone marrow failure, pulmonary fibrosis, and cirrhosis to determine the immunologic signature of their lymphocytes in each phenotype. We will apply technical expertise from each group utilizing mass cytometry (CyTOF), flow cytometry, and cytokine analysis. This study will strengthen the existing collaboration between USP and KCH in hematology for the understanding of the telomere diseases at the molecular level. (AU)

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