Our application is a pilot project focused on eliminating unexpected adverse effects of cancer therapeutics by uncovering health risk of a new class of immunotherapeutics that are in clinical and preclinical development. Receptor tyrosine kinase (RTK) genes Tyro3, Axl and Mertk are paralogs that have been newly characterized as “innate immune checkpoints”. The blockade of this class of RTKs is in development as immunotherapies that can boost anti-tumor immune response. However, here we provide preliminary data that some paralogs are expressed in astrocytes and microglia in the brain, and are functionally important for the maintenance of brain health and neurocognitive functions. Specifically, loss of function of Mertk and Axl in astrocytes did not affect early postnatal brain development (P45), but astrocytes expressed unfolded protein response-genes in mice by 3-months of age, concomitant with these astrocytes undergoing spontaneous activation. By 9-months of age, we observed lipofuscin accumulation in the brain. Although performance in learning and memory tasks was normal at 3- and 6-months of age, 9-month old mice displayed defects in hippocampus-dependent learning and memory. Furthermore, we also observed that ablation of Axl in microglia in an Alzheimer's Disease (AD) mouse model (5xFAD mouse) accelerated learning and memory defects in these mice. In light of this novel knowledge of the functional requirement AXL and MERTK in the brain, we believe it is imperative to fully investigate if targeting the kinase activity of these RTKs can have adverse neurocognitive effects. Since kinases primarily function through their enzymatic activity to phosphorylate substrates, we are choosing to take this approach first. Therefore, our application also includes the development of a new resource – AXL kinase- dead or AxlKD mouse. A MertkKD is already available in our laboratory. We will use these mouse models to investigate the effect of targeting kinase function in brain homeostasis, and learning and memory. We will also investigate AXL function in the context of an AD mouse model. Notably, our approach is essentially identical with the approach used to generate the preliminary data. The same set of experiments included in the preliminary data will be performed on MertkKD and/or AxlKD mice. We will perform the assays at various ages to characterize the age-dependent onset of the phenotypes. Observed histological changes in the brain in the MertkKD and/or AxlKD mice, along with behavioral changes in the animal, will not only provide a novel understanding of MERTK and AXL kinase in the brain health and neurocognitive function, but will also provide a rationale for developing brain-excluded therapeutics for AXL- and/or MERTK-based tumor immunotherapy. Kinase-independent, scaffold-functions of kinases have also been described to exist. This will be pursued in the future if our studies fail to reveal the phenotype observed with genetic knockout of Axl or that...