Cerebrovascular injuries, including overt stroke, silent cerebral infarction involving diffused white matter neuroaxonal lesions are integrated within the pathogenesis of vascular contributions to cognitive impairment and dementia (VCID). A significant disease burden in sickle cell disease (SCD) includes cognitive decline affecting >50% of the adult patients impacting memory and executive functioning primarily associated with white matter hyperintensities. Occlusions of the cerebral microvessels due to sickle hemoglobin polymerization results in hypoxia and subsequent reoxygenation (H/R) leading to ischemic tissue damage. The present proposal, set to determine the mechanistic link between H/R within the cerebrovascular space and the white matter hyperintensities instigating VCID in SCD setting, thus create a prototype to fill the knowledge gap in the pathogenesis of VCID. Using a preclinical mouse model of SCD, we found that microstructural white matter hyperintensities, identified by magnetic resonance imaging-based diffusion tensor imaging and histopathology are substantially abundant in sickle (SS) mice compared to normal (AA) mice. The white matter hyperintensities in the SS mice were associated with cognitive decline and activation of astrocytes, the modified glial cells connecting cerebral microvasculature and the neurons. Frataxin (FXN), a mitochondrial protein responsible for iron-sulfer clustering, regulates astrocyte function and is associated with neurodegeneration in Friedreich’s ataxia. Our pilot data showed that expression of FXN is reduced in the astrocytes concomitant with an increase in hypoxia inducible factor-1a (HIF-1a), a homeostatic regulatory transcription factor that is elevated during H/R events. The overarching scientific hypothesis is that elevated HIF-1a inhibits astrocytic frataxin and promotes white matter injury and VCID in SCD. In Aim 1, we will be performing diffusion tensor imaging and immunofluorescence experiments to assess microstructural damage, neuronal calcium accumulation and astrocyte activation in H/R-challenged SS and AA mice. Using bone marrow trasplantation (BMT), we will be assessing the role of FXN in the development of white matter injury and cognitive impairment following H/R injury in the sickle chimera mice lacking expression of astrocytic FXN. In Aim 2, a sickle chimera mice with targeted deletion of HIF-1a in the astrocytes will be generated using BMT. The new sickle chimera mice will be used to determine whether HIF-1a is critical for inhibition of FXN promoting white matter injury and cognitive decline. Successful completion of the study will identify FXN as a promising therapeutic target for white matter protection that may help provide resilience against VCID. Since underlying inflammation and ischemia often accelerate age-related pathophysiology in SCD, this study will lay the foundation to identify the causal link between ischemia and astrocyte function in the pathogenesis of progressive...