Mechanisms and Neuroprotective Targets in Alcohol-Induced Brain Injury

About This Grant

PROJECT SUMMARY Fetal Alcohol Spectrum Disorders (FASD) represent a major public health concern, significantly contributing to intellectual disabilities with a prevalence rate of 1-5% in the United States and an estimated annual economic burden of $5 billion. Despite its substantial impact, there is currently no cure for FASD. Existing research, including our own, indicates that various brain cells and regions exhibit differential vulnerability to alcohol-induced injury, with underlying mechanisms remaining poorly understood. For instance, neurons are particularly susceptible to alcohol stress, often undergoing acute apoptosis, and those that survive exhibit impaired functionality. Our primary goal is to elucidate the brain region- and cell-specific mechanisms underlying alcohol- induced developmental neurotoxicity (AIDN) and develop cell-specific precision interventions. By addressing the following critical questions, we aim to uncover novel targets for intervention: 1) Why are neurons more vulnerable to alcohol-induced injury? What neuron-specific signaling pathways contribute to this vulnerability? What are the brain region- and cell-specific targets for neuroprotection? To achieve these objectives, we will employ cutting- edge, multidisciplinary approaches including virus-based cell-specific gene modification, spatial transcriptomics, various imaging systems (e.g., multiphoton imaging), and various behavioral tests. Our research will utilize complementary models, including human induced pluripotent stem cell-derived 3D mini brains and mouse models, to investigate the mechanisms of AIDN at molecular, cellular, tissue, and animal levels. Additionally, we will assess the neuroprotective effects of neuron-specific and mitochondria-targeted interventions in AIDN. This study aims to provide a comprehensive understanding of the mechanisms driving alcohol-induced cognitive and behavioral impairments. By mapping acute and long-term brain region- and cell-type specific gene expression profiles following developmental alcohol exposure, our research offers promising strategies for early, brain cell type-targeted precision interventions and treatments for FASD patients. Moreover, the inclusion of human stem cell-based mini brain models will enhance the translational potential of our findings, potentially offering insights applicable to other neurodevelopmental disorders.