RESUMO
The recent shift of computational biologists from bioinformatics service providers to leaders of cutting-edge programs highlights the accompanying cultural and conceptual changes that should be implemented by funding bodies and academic institutions.
Assuntos
Biologia Computacional , Pesquisadores , Biologia/métodos , Biologia Computacional/métodos , Mineração de Dados , Sistemas de Gerenciamento de Base de Dados , Genômica/métodos , Humanos , Pesquisa , Recursos HumanosAssuntos
Pesquisa Biomédica/tendências , Ácidos e Sais Biliares/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Transmissíveis/transmissão , Terapia Genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Neoplasias , Técnicas de Transferência Nuclear , Publicações Periódicas como Assunto , Medicina RegenerativaRESUMO
Ependymal overexpression of brain-derived neurotrophic factor (BDNF) stimulates neuronal addition to the adult striatum, from subependymal progenitor cells. Noggin, by suppressing subependymal gliogenesis and increasing progenitor availability, potentiates this process. We asked whether BDNF/Noggin overexpression might be used to recruit new striatal neurons in R6/2 huntingtin transgenic mice. R6/2 mice injected with adenoviral BDNF and adenoviral Noggin (AdBDNF/AdNoggin) recruited BrdU(+)betaIII-tubulin(+) neurons, which developed as DARPP-32(+) and GABAergic medium spiny neurons that expressed either enkephalin or substance P and extended fibers to the globus pallidus. Only AdBDNF/AdNoggin-treated R6/2 mice harbored migrating doublecortin-defined neuroblasts in their striata, and the new neurons expressed p27 as a marker of mitotic quiescence after parenchymal integration. AdBDNF/AdNoggin-treated R6/2 mice sustained their rotarod performance and open-field activity and survived longer than did AdNull-treated and untreated controls. Neither motor performance nor survival improved in R6/2 mice treated only with AdBDNF, and intraventricular infusion of the mitotic inhibitor Ara-C completely blocked the performance and survival effects of AdBDNF/AdNoggin, suggesting that the benefits of AdBDNF/AdNoggin derived from neuronal addition. Thus, BDNF and Noggin induced striatal neuronal regeneration, delayed motor impairment, and extended survival in R6/2 mice, suggesting a new therapeutic strategy in Huntington disease.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Proteínas de Transporte/genética , Doença de Huntington/terapia , Neostriado/fisiologia , Neurônios/fisiologia , Regeneração , Adenoviridae/genética , Animais , Modelos Animais de Doenças , Progressão da Doença , Encefalinas/análise , Encefalinas/metabolismo , Globo Pálido/citologia , Globo Pálido/fisiologia , Doença de Huntington/fisiopatologia , Camundongos , Camundongos Transgênicos , Mitose , Neostriado/citologia , Neurônios/química , Neurônios/metabolismo , Substância P/análise , Substância P/metabolismo , Tubulina (Proteína)/metabolismoRESUMO
Neurogenesis from endogenous progenitor cells in the adult forebrain ventricular wall may be induced by the local viral overexpression of cognate neuronal differentiation agents, in particular BDNF. Here, we show that the overexpression of noggin, by acting to inhibit glial differentiation by subependymal progenitor cells, can potentiate adenoviral BDNF-mediated recruitment of new neurons to the adult rat neostriatum. The new neurons survive at least 2 months after their genesis in the subependymal zone and are recruited primarily as GABAergic DARPP-32+ medium spiny neurons in the caudate-putamen. The new medium spiny neurons successfully project to the globus pallidus, their usual developmental target, extending processes over several millimeters of the normal adult striatum. Thus, concurrent suppression of subependymal glial differentiation and promotion of neuronal differentiation can mobilize endogenous subependymal progenitor cells to achieve substantial neuronal addition to otherwise non-neurogenic regions of the adult brain.
Assuntos
Adenoviridae/genética , Proteínas Morfogenéticas Ósseas/biossíntese , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Neurônios/metabolismo , Células-Tronco/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Bromodesoxiuridina , Proteínas de Transporte , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Corantes Fluorescentes , Técnicas de Transferência de Genes , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Globo Pálido/citologia , Humanos , Ventrículos Laterais/citologia , Ventrículos Laterais/efeitos dos fármacos , Neostriado/citologia , Neostriado/efeitos dos fármacos , Neuroglia/citologia , Neuroglia/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , EstilbamidinasRESUMO
Neural progenitor cells are widespread throughout the adult central nervous system but only give rise to neurons in specific loci. Negative regulators of neurogenesis have therefore been postulated, but none have yet been identified as subserving a significant role in the adult brain. Here we report that nitric oxide (NO) acts as an important negative regulator of cell proliferation in the adult mammalian brain. We used two independent approaches to examine the function of NO in adult neurogenesis. In a pharmacological approach, we suppressed NO production in the rat brain by intraventricular infusion of an NO synthase inhibitor. In a genetic approach, we generated a null mutant neuronal NO synthase knockout mouse line by targeting the exon encoding active center of the enzyme. In both models, the number of new cells generated in neurogenic areas of the adult brain, the olfactory subependyma and the dentate gyrus, was strongly augmented, which indicates that division of neural stem cells in the adult brain is controlled by NO and suggests a strategy for enhancing neurogenesis in the adult central nervous system.