Project description:Microglia are important immune cells in the central nervous system (CNS). Dysfunctions of gene-deficient microglia contribute to the development and progression of multiple CNS diseases. Microglia replacement by nonself cells has been proposed to treat microglia associated disorders. However, most of attempts are failed due to low replacement efficiencies, such as with the traditional bone marrow transplantation approach. In this study, we develop three efficient strategies for microglia replacement: microglia replacement by bone marrow transplantation (mrBMT), microglia replacement by peripheral blood (mrPB) and microglia replacement by microglia transplantation (mrMT). mrBMT and mrPB allow microglia-like cells to efficiently replace resident microglia in the whole CNS. On the other hand, mrMT achieves microglia replacement in brain regions of interest. In summary, the present study offers effective tactics for microglia replacement with diverse application scenarios, which potentially opens up a window on treating microglia-associated CNS disorders.
Project description:RATIONALE: Radiolabeled monoclonal antibodies, such as iodine I 131 monoclonal antibody 3F8, can find tumor cells and carry tumor-killing substances to them without harming normal cells. This may be an effective treatment for central nervous system cancer or leptomeningeal metastases.
PURPOSE: This phase II trial is studying the side effects and how well iodine I 131 monoclonal antibody 3F8 works in treating patients with central nervous system cancer or leptomeningeal cancer.
Project description:The brown ghost knifefish (Apteronotus leptorhynchus) is a weakly electric teleost fish of particular interest as a model organism for a variety of research areas in neuroscience, including neurophysiology, neuroethology, and neurobiology. This versatile model system has been more recently used in the study of central nervous system development and regeneration during adulthood, as well as in the study of vertebrate aging and senescence. Despite substantial scientific interest in this species, no genomic resources are currently available. After evaluating several trimming and transcript reconstruction strategies, de novo assembly using Trinity uncovered at least 11,847 unique components (“genes”) containing full or near-full length protein sequences based on alignment to a reference set of known Actinopterygii protein sequences, with as many as 42,459 components containing at least a partial protein-coding sequence, providing broad coverage of the proteome. Shotgun proteomics confirmed translation of open reading frames from over 2,000 transcripts, including alternative splice variants. Assignment of tandem mass spectra obtained was shown to be greatly improved with the assembly compared with using databases of sequences from closely related organisms.
Project description:Myelin is required for the function of neuronal axons in the central nervous system, yet the mechanisms supporting myelin health are unclear. Although central nervous system macrophages have been implicated, it is unknown which macrophage populations are involved and which aspects of myelin health they influence. Here, we show that resident microglia are critical for the maintenance of myelin health in adulthood in both mouse and human. We demonstrate that whereas microglia are dispensable for developmental myelin ensheathment, they are required for subsequent regulation of myelin growth and associated cognitive function, and for the preservation of myelin integrity by preventing its degeneration. We discovered that loss of myelin health in the absence of microglia is underpinned by the appearance of a myelinating oligodendrocyte subpopulation with altered lipid metabolism, regulated by a disruption of the TGFβ1-TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions where myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease.
Project description:Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand. Here, we show that interaction between glial cells – astrocytes and mature myelin-forming oligodendrocytes – is a critical determinant of remyelination. Using in vivo/ ex vivo/ in vitro rodent models and human brain lesion analyses, we discover that astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation in focally-lesioned mice yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.
Project description:As tissue macrophages of the central nervous system (CNS), microglia are critically involved in diseases of the CNS. However, it remains unknown what controls their maturation and activation under homeostatic conditions. Here we reveal significant contributions of the host microbiota to microglia homeostasis as germ-free (GF) mice displayed global defects in microglia with altered cell proportions and an immature phenotype leading to impaired innate immune responses. Temporal eradication of host microbiota severely changed microglia properties. Limited microbiota complexity also resulted in defective microglia. In contrast, recolonization with a complex microbiota partially restored microglia features. We determined that short-chain fatty acids (SCFA), microbiota-derived bacterial fermentation products, regulate microglia homeostasis. Accordingly, mice deficient for the SCFA receptor FFAR2 mirrored microglia defects found under GF conditions. These findings reveal that host bacteria vitally regulate microglia maturation and function, whereas microglia impairment can be restored to some extent by complex microbiota. For acute inflammatory challenges, LPS was applied intracranially and 6 hours later, animals were analyzed. Control animals were injected PBS i.c. Transcriptional profiles of FACS-sorted microglia were assessed using Affymetrix® (Santa Clara, USA) GeneChip Arrays (Mouse Gene 2.1 ST Arrays).
Project description:We report the application of single-molecule-based sequencing technology for high-throughput profiling of nervous system in locust Locusta migratoria manilensis. By obtaining over 57,000,000 bases of sequence from central nervous system, we generated 101836 contigs and 69440 scaffolds. We finally get 41179 unigene with an average length of 570bp. There are 5519 unigenes beyond the length of 1000bp. Using BLAST searches of the NR, NT, Swiss-Prot, KEGG and COG databases we are able to identify 13552 unigene (E<0.0001). Comprehensive assessment of all the unigenes by comparing with the studied genes of other insects nervous system reveals that our unigene are broadly representative of the transcriptome of insect nervous system. Our data provides the most large-scale EST-project for locust nervous system, which greatly benefits the exploring of this insect. In addition, we identify a large number of novel nervous genes which can be used in systematic studies of locust and other insects. Examination of 1 sample