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1.
PLoS Genet ; 13(6): e1006848, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28617813

RESUMO

Recent findings indicate that growth factor-driven angiogenesis is markedly influenced by genetic variation. This variation in angiogenic responsiveness may alter the susceptibility to a number of angiogenesis-dependent diseases. Here, we utilized the genetic diversity available in common inbred mouse strains to identify the loci and candidate genes responsible for differences in angiogenic response. The corneal micropocket neovascularization assay was performed on 42 different inbred mouse strains using basic fibroblast growth factor (bFGF) pellets. We performed a genome-wide association study utilizing efficient mixed-model association (EMMA) mapping using the induced vessel area from all strains. Our analysis yielded five loci with genome-wide significance on chromosomes 4, 8, 11, 15 and 16. We further refined the mapping on chromosome 4 within a haplotype block containing multiple candidate genes. These genes were evaluated by expression analysis in corneas of various inbred strains and in vitro functional assays in human microvascular endothelial cells (HMVECs). Of these, we found the expression of peptidyl arginine deiminase type II (Padi2), known to be involved in metabolic pathways, to have a strong correlation with a haplotype shared by multiple high angiogenic strains. In addition, inhibition of Padi2 demonstrated a dosage-dependent effect in HMVECs. To investigate its role in vivo, we knocked down Padi2 in transgenic kdrl:zsGreen zebrafish embryos using morpholinos. These embryos had disrupted vessel formation compared to control siblings. The impaired vascular pattern was partially rescued by human PADI2 mRNA, providing evidence for the specificity of the morphant phenotype. Taken together, our study is the first to indicate the potential role of Padi2 as an angiogenesis-regulating gene. The characterization of Padi2 and other genes in associated pathways may provide new understanding of angiogenesis regulation and novel targets for diagnosis and treatment of a wide variety of angiogenesis-dependent diseases.


Assuntos
Estudo de Associação Genômica Ampla , Hidrolases/genética , Neovascularização Patológica/genética , Animais , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fator 2 de Crescimento de Fibroblastos/genética , Variação Genética , Haplótipos , Humanos , Hidrolases/biossíntese , Camundongos , Camundongos Endogâmicos , Fenótipo , Proteína-Arginina Desiminase do Tipo 2 , Desiminases de Arginina em Proteínas , Peixe-Zebra
2.
Am J Hum Genet ; 100(1): 51-63, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28017375

RESUMO

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.


Assuntos
Eritrócitos/metabolismo , Eritropoese/genética , Proteínas de Ligação a RNA/genética , Grupos Raciais/genética , África/etnologia , Alelos , Animais , Teorema de Bayes , Etnicidade/genética , Europa (Continente)/etnologia , Ásia Oriental/etnologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Peixe-Zebra/genética
3.
Nature ; 508(7494): 103-107, 2014 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-24670641

RESUMO

Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2) and its substrate XBP1 (ref. 3). Previous studies report UPR activation in various human tumours, but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. Triple-negative breast cancer (TNBC)--a form of breast cancer in which tumour cells do not express the genes for oestrogen receptor, progesterone receptor and HER2 (also called ERBB2 or NEU)--is a highly aggressive malignancy with limited treatment options. Here we report that XBP1 is activated in TNBC and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumour growth and tumour relapse and reduced the CD44(high)CD24(low) population. Hypoxia-inducing factor 1α (HIF1α) is known to be hyperactivated in TNBCs. Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fatores de Transcrição/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Antígeno CD24/metabolismo , Hipóxia Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Inativação Gênica , Humanos , Receptores de Hialuronatos/metabolismo , Camundongos , Invasividade Neoplásica , Recidiva Local de Neoplasia , Prognóstico , RNA Polimerase II/metabolismo , Fatores de Transcrição de Fator Regulador X , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Transcrição Gênica , Neoplasias de Mama Triplo Negativas/irrigação sanguínea , Neoplasias de Mama Triplo Negativas/genética , Resposta a Proteínas não Dobradas , Proteína 1 de Ligação a X-Box
4.
J Exp Med ; 207(5): 923-31, 2010 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-20421389

RESUMO

Patients taking immunosuppressive drugs, like cyclosporine A (CsA), that inhibit calcineurin are highly susceptible to disseminated fungal infections, although it is unclear how these drugs suppress resistance to these opportunistic pathogens. We show that in a mouse model of disseminated Candida albicans infection, CsA-induced susceptibility to fungal infection maps to the innate immune system. To further define the cell types targeted by CsA, we generated mice with a conditional deletion of calcineurin B (CnB) in neutrophils. These mice displayed markedly decreased resistance to infection with C. albicans, and both CnB-deficient and CsA-treated neutrophils showed a defect in the ex vivo killing of C. albicans. In response to the fungal-derived pathogen-associated molecular pattern zymosan, neutrophils lacking CnB displayed impaired up-regulation of genes (IL-10, Cox2, Egr1, and Egr2) regulated by nuclear factor of activated T cells, the best characterized CnB substrate. This activity was Myd88 independent and was reproduced by stimulation with the beta(1,3) glucan curdlan, indicating that dectin-1, rather than toll-like receptors, is the upstream activator of calcineurin. Our results suggest that disseminated fungal infections seen in CsA-treated patients are not just a general consequence of systemic suppression of adaptive immunity but are, rather, a result of the specific blockade of evolutionarily conserved innate pathways for fungal resistance.


Assuntos
Antifúngicos/imunologia , Calcineurina/fisiologia , Candidíase/epidemiologia , Micoses/epidemiologia , Neutrófilos/imunologia , Animais , Calcineurina/deficiência , Calcineurina/efeitos dos fármacos , Calcineurina/genética , Candida albicans , Candidíase/imunologia , Ciclosporina/efeitos adversos , Ciclosporina/uso terapêutico , Suscetibilidade a Doenças , Homeostase , Humanos , Imunidade Inata/efeitos dos fármacos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Camundongos , Micoses/imunologia , Neutrófilos/microbiologia , Neutrófilos/fisiologia , Polissacarídeos Bacterianos/farmacologia , Zimosan/farmacologia , beta-Glucanas/farmacologia
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