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1.
Nat Commun ; 14(1): 5683, 2023 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-37709737

RESUMO

The biologic basis of genetic ancestry-dependent variability in disease incidence and outcome is just beginning to be explored. We recently reported enrichment of a population of ZEB1-expressing cells located adjacent to ductal epithelial cells in normal breasts of women of African ancestry compared to those of European ancestry. In this study, we demonstrate that these cells have properties of fibroadipogenic/mesenchymal stromal cells that express PROCR and PDGFRα and transdifferentiate into adipogenic and osteogenic lineages. PROCR + /ZEB1 + /PDGFRα+ (PZP) cells are enriched in normal breast tissues of women of African compared to European ancestry. PZP: epithelial cell communication results in luminal epithelial cells acquiring basal cell characteristics and IL-6-dependent increase in STAT3 phosphorylation. Furthermore, level of phospho-STAT3 is higher in normal and cancerous breast tissues of women of African ancestry. PZP cells transformed with HRasG12V ± SV40-T/t antigens generate metaplastic carcinoma suggesting that these cells are one of the cells-of-origin of metaplastic breast cancers.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Incidência , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Receptor de Proteína C Endotelial , Receptor alfa de Fator de Crescimento Derivado de Plaquetas , Células Epiteliais
2.
JCI Insight ; 8(9)2023 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-36976647

RESUMO

Loss-of-function mutations in the DNA methyltransferase 3A (DNMT3A) are seen in a large number of patients with acute myeloid leukemia (AML) with normal cytogenetics and are frequently associated with poor prognosis. DNMT3A mutations are an early preleukemic event, which - when combined with other genetic lesions - result in full-blown leukemia. Here, we show that loss of Dnmt3a in hematopoietic stem and progenitor cells (HSC/Ps) results in myeloproliferation, which is associated with hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway. PI3Kα/ß or the PI3Kα/δ inhibitor treatment partially corrects myeloproliferation, although the partial rescue is more efficient in response to the PI3Kα/ß inhibitor treatment. In vivo RNA-Seq analysis on drug-treated Dnmt3a-/- HSC/Ps showed a reduction in the expression of genes associated with chemokines, inflammation, cell attachment, and extracellular matrix compared with controls. Remarkably, drug-treated leukemic mice showed a reversal in the enhanced fetal liver HSC-like gene signature observed in vehicle-treated Dnmt3a-/- LSK cells as well as a reduction in the expression of genes involved in regulating actin cytoskeleton-based functions, including the RHO/RAC GTPases. In a human PDX model bearing DNMT3A mutant AML, PI3Kα/ß inhibitor treatment prolonged their survival and rescued the leukemic burden. Our results identify a potentially new target for treating DNMT3A mutation-driven myeloid malignancies.


Assuntos
DNA (Citosina-5-)-Metiltransferases , Leucemia Mieloide Aguda , Humanos , Camundongos , Animais , DNA (Citosina-5-)-Metiltransferases/genética , Fosfatidilinositol 3-Quinases/genética , DNA Metiltransferase 3A , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Células Mieloides/patologia , Homeostase
3.
Neurobiol Aging ; 32(12): 2319.e27-34, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20570407

RESUMO

Alzheimer's disease (AD) is a common cause of dementia with a strong genetic component and risk sharply increasing with age. We performed two parallel microarray experiments to independently identify genes involved in normal aging and genes involved in AD using RNA extracted from the temporal lobe of 22 late onset AD and 23 control brain donors. We found that AD is accompanied by significant changes in the expression of many genes with upregulation of genes involved in inflammation and in transcription regulation and downregulation of genes involved in neuronal functions. The changes with healthy aging involved multiple genes but were not as strong. Replicating and strengthening previous reports, we find a highly significant overlap between genes changing expression with age and those changing in AD, and we observe that those changes are most often in the same direction. This result supports an overlap between the biological processes of normal aging and susceptibility to AD and suggests that age related genes expression changes might increase the risk of developing AD.


Assuntos
Envelhecimento/genética , Doença de Alzheimer/genética , Regulação da Expressão Gênica/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Doença de Alzheimer/patologia , Química Encefálica/genética , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Serial de Proteínas/métodos
4.
Neurogenetics ; 11(3): 335-48, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20182759

RESUMO

We have previously reported strong linkage on chromosome 10q in pedigrees transmitting Alzheimer's disease through the mother, overlapping with many significant linkage reports including the largest reported study. Here, we report the most comprehensive fine mapping of this region to date. In a sample of 638 late-onset Alzheimer's disease (LOAD) cases and controls including 104 maternal LOAD cases, we genotyped 3,884 single nucleotide polymorphisms (SNPs) covering 15.2 Mb. We then used imputations and publicly available data to generate an extended dataset including 4,329 SNPs for 1,209 AD cases and 839 controls in the same region. Further, we screened eight genes in this region for rare alleles in 283 individuals by nucleotide sequencing, and we tested for possible monoallelic expression as it might underlie our maternal parent of origin linkage. We excluded the possibility of multiple rare coding risk variants for these genes and monoallelic expression when we could test for it. One SNP, rs10824310 in the PRKG1 gene, showed study-wide significant association without a parent of origin effect, but the effect size estimate is not of sufficient magnitude to explain the linkage, and no association is observed in an independent genome-wide association studies (GWAS) report. Further, no causative variants were identified though sequencing. Analysis of cases with maternal disease origin pointed to a few regions of interest that included the genes PRKG1 and PCDH15 and an intergenic interval of 200 Kb. It is likely that non-transcribed rare variants or other mechanisms involving these genomic regions underlie the observed linkage and parent of origin effect. Acquiring additional support and clarifying the mechanisms of such involvement is important for AD and other complex disorder genetics research.


Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 10/genética , Ligação Genética , Predisposição Genética para Doença , Idoso , Proteínas Relacionadas a Caderinas , Caderinas/genética , Mapeamento Cromossômico , Feminino , Loci Gênicos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
5.
Neurobiol Aging ; 31(11): 1835-42, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19010568

RESUMO

We previously reported strong genetic linkage on chromosome 14q to Alzheimer's disease (AD) using the presence of co-morbid hallucinations as a covariate. Those results suggested the presence of a gene increasing the risk for a genetically homogeneous form of AD characterized by the absence of comorbid hallucinations. Here we report our follow up of that study through the analysis of single nucleotide polymorphisms (SNPs) in five functional candidate genes. This work provides significant evidence of association for the gene coding for neuroglobin (NGB), a nervous system globin known to protect cells against amyloid toxicity and to attenuate the AD phenotype of transgenic mice. On further experiments we found that NGB expression is reduced with increasing age and lower in women consistent with their increased risk. NGB expression is up-regulated in the temporal lobe of AD patients consistent with a response to the disease process, as reported for NGB and hypoxia. We speculate that a compromised response due to DNA variation might increase the risk for AD. Our and others' data strongly support the involvement of NGB in AD.


Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 14/genética , Globinas/genética , Alucinações/genética , Proteínas do Tecido Nervoso/genética , Transtornos Psicóticos/genética , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Estudos de Casos e Controles , Feminino , Seguimentos , Globinas/metabolismo , Alucinações/complicações , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Neuroglobina , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/complicações , Valores de Referência , Fatores Sexuais , Lobo Temporal/metabolismo
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