Researcher(s)
- Alison Ramirez, Biological Sciences, University of Delaware
Faculty Mentor(s)
- Amanda Hernan, Psychological and Brain Sciences, University of Delaware
Abstract
Tuberous sclerosis complex, or TSC, is an autosomal dominant syndrome that is characterized by structural brain malformations, epilepsy, and intellectual disabilities. TSC affects about 1 in 6,000 individuals, and epilepsy affects up to 80% of patients. TSC is caused by mutations in either the TSC1 or TSC2 gene. More importantly, patients with the same inherited gene mutation in the TSC1 or TSC2 gene can have vastly different outcomes. Which suggests that there are gene modifiers in the genetic background that can be exploited to improve outcome for TSC patients. Subependymal giant cell astrocytomas are rare, benign, brain tumors that originate in astrocytes and are almost exclusively in patients with TSC. The presence of SEGA’s in TSC patients highlights the importance of studying astrocytes in the disease. Astrocytes are a type of glial cell in the brain. They are actively involved in things like neurotransmitter uptake, neuron & synapse development, they maintain ionic homeostasis, respond to brain injury, and they help to maintain the blood brain barrier. We looked at the expression of proteins that are involved in key astrocytic pathways. Regarding astrocytes, mouse strain-dependent differences in astrocytes have been established. The diversity outbred panel is a large panel of recently established multi parental recombinant inbred mouse lines that is designed to test for genetic background effects that modify disease outcome. Strains from the DO founders show differences in the number of astrocytes in the hippocampus, and evidence exists that there are big differences in the expression of key astrocytic proteins that should manifest as functional differences between the diversity outbred founder mouse strains. There’s strong evidence that indicates the presence of strain dependent functional heterogeneity in astrocytes in the diversity outbred panel. By exploiting this heterogeneity, we were able to test the hypothesis that astrocytes are crucial drivers of TSC outcomes.