RESUMEN
We have developed an efficient, streamlined, cost-effective approach to obtain Investigational New Drug (IND) approvals from the Food and Drug Administration (FDA) for positron emission tomography (PET) imaging probes (while the FDA uses the terminology PET drugs, we are using "PET imaging probes," "PET probes," or "probes" as the descriptive terms). The required application and supporting data for the INDs were collected in a collaborative effort involving appropriate scientific disciplines. This path to INDs was successfully used to translate three [(18) F]fluoro-arabinofuranosylcytosine (FAC) analog PET probes to phase 1 clinical trials. In doing this, a mechanism has been established to fulfill the FDA regulatory requirements for translating promising PET imaging probes from preclinical research into human clinical trials in an efficient and cost-effective manner.
Asunto(s)
Academias e Institutos , Drogas en Investigación , Imagen Molecular , Sondas Moleculares , Tomografía de Emisión de Positrones , Animales , Citarabina , Aprobación de Drogas , Femenino , Humanos , Masculino , Imagen Molecular/economía , Sondas Moleculares/economía , Tomografía de Emisión de Positrones/economía , Ratas Sprague-Dawley , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Delta-catenin is a brain-specific member of the adherens junction complex that localizes to the postsynaptic and dendritic compartments. This protein is likely critical for normal cognitive function; its hemizygous loss is linked to the severe mental retardation syndrome Cri-du-Chat and it directly interacts with presenilin-1 (PS1), the protein most frequently mutated in familial Alzheimer's disease. Here we examine dendritic structure and cortical function in vivo in mice lacking delta-catenin. We find that in cerebral cortex of 5-week-old mice, dendritic complexity, spine density, and cortical responsiveness are similar between mutant and littermate controls; thereafter, mutant mice experience progressive dendritic retraction, a reduction in spine density and stability, and concomitant reductions in cortical responsiveness. Our results indicate that delta-catenin regulates the maintenance of dendrites and dendritic spines in mature cortex but does not appear to be necessary for the initial establishment of these structures during development.
Asunto(s)
Moléculas de Adhesión Celular/metabolismo , Corteza Cerebral/fisiología , Dendritas/fisiología , Neuronas/fisiología , Fosfoproteínas/metabolismo , Envejecimiento , Animales , Cateninas , Moléculas de Adhesión Celular/genética , Tamaño de la Célula , Corteza Cerebral/citología , Corteza Cerebral/crecimiento & desarrollo , Espinas Dendríticas/fisiología , Estimulación Eléctrica , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Cinética , Ratones , Ratones Transgénicos , Microelectrodos , Mutación , Neuronas/citología , Fosfoproteínas/genética , Células Piramidales/citología , Células Piramidales/fisiología , Corteza Visual/citología , Corteza Visual/crecimiento & desarrollo , Corteza Visual/fisiología , Catenina deltaRESUMEN
Erythropoietin (EPO) is the principal growth factor regulating the production of red blood cells. Recent studies demonstrated that exogenous EPO acts as a neuroprotectant and regulates neurogenesis. Using a genetic approach, we evaluate the roles of endogenous EPO and its classical receptor (EPOR) in mammalian neurogenesis. We demonstrate severe and identical embryonic neurogenesis defects in animals null for either the Epo or EpoR gene, suggesting that the classical EPOR is essential for EPO action during embryonic neurogenesis. Furthermore, by generating conditional EpoR knock-down animals, we demonstrate that brain-specific deletion of EpoR leads to significantly reduced cell proliferation in the subventricular zone and impaired post-stroke neurogenesis. EpoR conditional knockdown leads to a specific deficit in post-stroke neurogenesis through impaired migration of neuroblasts to the peri-infarct cortex. Our results suggest that both EPO and EPOR are essential for early embryonic neural development and that the classical EPOR is important for adult neurogenesis and for migration of regenerating neurons during post-injury recovery.