PROJECT SUMMARY Lipid dysregulation is emerging as a critical component of neurodevelopmental disorders, such as Rett syndrome (RTT). RTT is an X-linked dominant disorder caused primarily by mutations in the methyl-CpG binding protein 2 (MECP2) gene, and predominantly affects females who are mosaic for MECP2 expression due to X-inactivation. RTT is characterized by apparently normal development in infancy, followed by rapid decline of motor and speech functions at 6-18 months of age. In addition to neurological effects, RTT is increasingly recognized as a multi-system disorder, affecting the lungs, intestinal tract, immune system, and lipid metabolism. Recent human and animal studies have strongly indicated a significant role for lipid metabolism in RTT pathology and disease progression. Exciting new preliminary data from a mouse model of RTT suggests a new role for lipids: lipid malabsorption in the intestinal tract. Lipids are crucial for the developing brain. Thus, lipid malabsorption could have detrimental effects on neurodevelopment. Lipid malabsorption can be corrected using nutritional therapies, presenting a potential opportunity for RTT treatment. Furthermore, our preliminary data point to lipid malabsorption as a female-specific effect. Mosaic females are the relevant clinical model, but previous studies in mice have largely focused on males completely deficient in Mecp2. The research outlined in this fellowship proposal will therefore use an established mouse model of RTT disease progression to evaluate whether lipid dysregulation mediates RTT disease progression in female mosaic mice using two specific aims: 1) evaluate the contribution of lipid malabsorption to RTT symptom progression and 2) examine the intersection of lipid and gene expression dysregulation in the brain of RTT female mice. The findings from this research will refine the role of lipid dysregulation in RTT disease progression and provide new avenues of treatment. The PI will train at a world-renowned research university under Sponsor Dr. Janine LaSalle and Co-Sponsor Dr. Ameer Taha to learn new skills and techniques to carry out this proposed research, including genetic mouse models of neurodevelopmental disorders, single-cell transcriptomics, targeted lipidomics, and bioinformatic data analysis and integration. These research skills will allow the PI to build on her background in studying the developmental origins of metabolic disease towards future independent research at the intersection of neurodevelopment and lipid metabolism. In addition to new research skills, the PI’s Sponsor will mentor her in obtaining professional development goals that will be instrumental in the PI’s trajectory towards a career as an independent researcher: 1) maximize leadership and management experience, hone skills at building an inclusive and diverse research environment, 3) improve scientific communication skills, and 4) build a network of future collaborators. Together, the research...