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 and
training plan in this proposal will prepare the PI for a successful career as an independent researcher.