This project concerns studies of brain mitogens and morphogens for astrocytes (substances promoting astrocytic proliferation and morphological changes, respectively), and their respective inhibitors. The studies are to be first carried out in a developmental and age-related fashion using in vitro models, followed by investigations of the effects of various types of brain injury on their potency in extracts. Three sets of experiments are proposed. In the first set, the effect of mitogens/morphogens on the proliferation and morphology of primary cultures of astrocytes will be studied by 3H-TdR uptake and cell counting, and by microscopy, respectively. Preliminary studies using Sprague-Dawley rats suggest that the the mitogenic effect of rat brain extracts varies with age. The data are interpreted to suggest that there are at least two astrocytic mitogens in brain, as well as varying amounts of inhibitors of the mitogens, and that in older animals the inhibition is relatively suppressed. Confirm-ation of these results will be sought in Fischer 344 rats, the strain of choice in subsequent experiments. Similar preliminary data is presented for the presence of morphogens in the extracts. It is proposed to seek evidence for similar results using brain extracts from other species, including human, on the rat astrocyte cultures. The second set of experiments would look at some of the molecular aspects of the factors. Some preliminary data has been gathered on size filtration, and temperature, pH, and trypsin sensitivity, and salt precipitation and ion exchange binding studies are proposed. The third set of experiments involves the effects of experimental brain injury on the levels and characteristics of the mitogen, morphogen, and inhibitor activities. Preliminary data suggest that mitogens increase after a brain lesion, at least in the gel-foam filled wound cavity (the puported tissue response was perhaps less convincing). The time course is to be repeated using Fisher rats, including dose-response analyses. The influence of distance from the wound, brain area, and type of lesion will be examined. It is proposed that the study can then be extended to in vivo analyses by the injection of mitogen-containing extracts.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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University of California Irvine
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Sosna, Justyna; Philipp, Stephan; Albay 3rd, Ricardo et al. (2018) Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer's disease. Mol Neurodegener 13:11
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