Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
2.
J Biochem ; 175(5): 551-560, 2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38168819

RESUMO

Lymphedema has become a global health issue following the growing number of cancer surgeries. Curative or supportive therapeutics have long been awaited for this refractory condition. Transcription factor GATA2 is crucial in lymphatic development and maintenance, as GATA2 haploinsufficient disease often manifests as lymphedema. We recently demonstrated that Gata2 heterozygous deficient mice displayed delayed lymphatic recanalization upon lymph node resection. However, whether GATA2 contributes to lymphatic regeneration by functioning in the damaged lymph vessels' microenvironment remains explored. In this study, our integrated analysis demonstrated that dermal collagen fibers were more densely accumulated in the Gata2 heterozygous deficient mice. The collagen metabolism-related transcriptome was perturbed, and collagen matrix contractile activity was aberrantly increased in Gata2 heterozygous embryonic fibroblasts. Notably, soluble collagen placement ameliorated delayed lymphatic recanalization, presumably by modulating the stiffness of the extracellular matrix around the resection site of Gata2 heterozygous deficient mice. Our results provide valuable insights into mechanisms underlying GATA2-haploinsufficiency-mediated lymphedema and shed light on potential therapeutic avenues for this intractable disease.


Assuntos
Colágeno , Fator de Transcrição GATA2 , Heterozigoto , Linfedema , Animais , Camundongos , Fator de Transcrição GATA2/metabolismo , Fator de Transcrição GATA2/genética , Linfedema/metabolismo , Linfedema/genética , Linfedema/patologia , Colágeno/metabolismo , Vasos Linfáticos/metabolismo , Vasos Linfáticos/patologia , Camundongos Knockout , Haploinsuficiência , Deficiência de GATA2/metabolismo , Deficiência de GATA2/genética , Camundongos Endogâmicos C57BL
3.
Hypertension ; 79(11): 2493-2504, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36043416

RESUMO

BACKGROUND: Natural killer (NK) cell impairment is a feature of pulmonary arterial hypertension (PAH) and contributes to vascular remodeling in animal models of disease. Although mutations in BMPR2, the gene encoding the BMP (bone morphogenetic protein) type-II receptor, are strongly associated with PAH, the contribution of BMPR2 loss to NK cell impairment remains unknown. We explored the impairment of IL (interleukin)-15 signaling, a central mediator of NK cell homeostasis, as both a downstream target of BMPR2 loss and a contributor to the pathogenesis of PAH. METHODS: The expression, trafficking, and secretion of IL-15 and IL-15Rα (interleukin 15 α-type receptor) were assessed in human pulmonary artery endothelial cells, with or without BMPR2 silencing. NK cell development and IL-15/IL-15Rα levels were quantified in mice bearing a heterozygous knock-in of the R899X-BMPR2 mutation (bmpr2+/R899X). NK-deficient Il15-/- rats were exposed to the Sugen/hypoxia and monocrotaline models of PAH to assess the impact of impaired IL-15 signaling on disease severity. RESULTS: BMPR2 loss reduced IL-15Rα surface presentation and secretion in human pulmonary artery endothelial cells via impaired trafficking through the trans-Golgi network. bmpr2+/R899X mice exhibited a decrease in NK cells, which was not attributable to impaired hematopoietic development but was instead associated with reduced IL-15/IL-15Rα levels in these animals. Il15-/- rats of both sexes exhibited enhanced disease severity in the Sugen/hypoxia model, with only male Il15-/- rats developing more severe PAH in response to monocrotaline. CONCLUSIONS: This work identifies the loss of IL-15 signaling as a novel BMPR2-dependent contributor to NK cell impairment and pulmonary vascular disease.


Assuntos
Deficiência de GATA2 , Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Humanos , Feminino , Masculino , Ratos , Camundongos , Animais , Hipertensão Pulmonar/etiologia , Interleucina-15/genética , Interleucina-15/metabolismo , Monocrotalina , Células Endoteliais/metabolismo , Deficiência de GATA2/complicações , Deficiência de GATA2/metabolismo , Deficiência de GATA2/patologia , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Artéria Pulmonar/metabolismo , Hipóxia/metabolismo
4.
J Clin Invest ; 129(3): 1180-1192, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30620726

RESUMO

The development and function of stem and progenitor cells that produce blood cells are vital in physiology. GATA-binding protein 2 (GATA2) mutations cause GATA-2 deficiency syndrome involving immunodeficiency, myelodysplastic syndrome, and acute myeloid leukemia. GATA-2 physiological activities necessitate that it be strictly regulated, and cell type-specific enhancers fulfill this role. The +9.5 intronic enhancer harbors multiple conserved cis-elements, and germline mutations of these cis-elements are pathogenic in humans. Since mechanisms underlying how GATA2 enhancer disease mutations impact hematopoiesis and pathology are unclear, we generated mouse models of the enhancer mutations. While a multi-motif mutant was embryonically lethal, a single-nucleotide Ets motif mutant was viable, and steady-state hematopoiesis was normal. However, the Ets motif mutation abrogated stem/progenitor cell regeneration following stress. These results reveal a new mechanism in human genetics, in which a disease predisposition mutation inactivates enhancer regenerative activity, while sparing developmental activity. Mutational sensitization to stress that instigates hematopoietic failure constitutes a paradigm for GATA-2 deficiency syndrome and other contexts of GATA-2-dependent pathogenesis.


Assuntos
Elementos Facilitadores Genéticos , Deficiência de GATA2 , Fator de Transcrição GATA2 , Mutação em Linhagem Germinativa , Hematopoese/genética , Motivos de Nucleotídeos , Regeneração/genética , Animais , Deficiência de GATA2/genética , Deficiência de GATA2/metabolismo , Fator de Transcrição GATA2/genética , Fator de Transcrição GATA2/metabolismo , Humanos , Camundongos , Camundongos Mutantes
5.
Hematol Oncol Clin North Am ; 32(4): 713-728, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30047422

RESUMO

GATA2 deficiency is an immunodeficiency and bone marrow failure disorder caused by pathogenic variants in GATA2. It is inherited in an autosomal-dominant pattern or can be due to de novo sporadic germline mutation. Patients commonly have B-cell, dendritic cell, natural killer cell, and monocytopenias, and are predisposed to myelodysplastic syndrome, acute myeloid leukemia, and chronic myelomonocytic leukemia. Patients may suffer from disseminated human papilloma virus and mycobacterial infections, pulmonary alveolar proteinosis, and lymphedema. The bone marrow eventually takes on a characteristic hypocellular myelodysplasia with loss of monocytes and hematogones, megakaryocytes with separated nuclear lobes, micromegakaryocytes, and megakaryocytes with hypolobated nuclei.


Assuntos
Anemia Aplástica , Doenças da Medula Óssea , Deficiência de GATA2 , Fator de Transcrição GATA2/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Hemoglobinúria Paroxística , Anemia Aplástica/genética , Anemia Aplástica/metabolismo , Anemia Aplástica/patologia , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/metabolismo , Doenças da Medula Óssea/patologia , Transtornos da Insuficiência da Medula Óssea , Deficiência de GATA2/genética , Deficiência de GATA2/metabolismo , Deficiência de GATA2/patologia , Hemoglobinúria Paroxística/genética , Hemoglobinúria Paroxística/metabolismo , Hemoglobinúria Paroxística/patologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA