Investigative Studies into mTORC1-Dependent Dendritic Branch Potentiation in TSC
Abstract
Overview and Impact: Neuropsychiatric characteristics among individuals with with tuberous sclerosis complex (TSC) are variable, complicating treatment strategies. Here, we address two Tuberous Sclerosis Complex Research Program high priority areas: (1) Understanding phenotypic heterogeneity in TSC that might explain why TSC is so different from person to person and (2) gaining a deeper knowledge of TSC signaling pathways and the cellular consequences of TSC deficiency. The proposed studies aim to provide insight into why the recent clinical study testing the mTOR inhibitor everolimus failed to show a statistically significant improvement in neurocognitive functioning in TSC children. Many patients with TSC have long-term memory impairment. Yet, the underlying molecular mechanism leading to cognitive deficits is not well understood. Memories are thought to be stored at synapses, requiring the protein composition to be remodeled to strengthen communication. The proposed studies utilize novel molecular tools to address (1) how proteins that are predicted to prevent memory formation are overexpressed at synapses in preclinical models of TSC and (2) what their physiological impacts are in a cellular model of memory. Of note, in the clinically relevant population (TSC2 heterozygotes, with one functioning copy of the gene tsc2), these proteins separate into two significantly different groups - those that have normal levels and those that reflect the knockout condition. Importantly, Food and Drug Administration (FDA)-approved modulators of these proteins are currently available. Based on the outcomes of these studies (3-year award period), future work will include repurposing these FDA-approved drugs, avoiding the typical 20-year timeframe required to move a drug from the “bench to the bedside.” Overall, these studies provide the foundation for the development of mechanism-based therapies for neurocognitive deficits in TSC children.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910202
Entities
People
- Kimberly F Raab-Graham
Organizations
- United States Army
- Wake Forest University