Dissecting Mechanisms Underlying Brain Calcification in TSC
Abstract
Tuberous sclerosis (TSC) is a genetic disorder that affects multiple organ systems including the brain. Epilepsy remains one of the most debilitating features of the disorder. As epilepsy progresses in a subset of patients, it can no longer be managed with medications. The scientific community does not have a good understanding of why or how epilepsy in TSC progresses into a more severe, untreatable form. Interestingly, several reports have shown that TSC patients with intractable epilepsy also develop calcium deposits associated with localized areas in their brains called tubers, which are often sites where seizures start. Further, several studies have linked brain calcification with the breakdown of the blood-brain barrier (BBB). The BBB consists of many cells types that allow it to selectively filter components of the blood into the brain. It is thought that these calcium deposits may underlie why some patients stop responding to antiseizure medications, although more research is needed to understand the relationships between BBB dysfunction, brain calcification, and intractable epilepsy. This proposal addresses the FY20 TSCRP Focus Area: “Preventing epilepsy, improving treatment, and mitigating comorbidities associated with TSC-related seizures.” Our preliminary data point to molecular changes in pericytes and other perivascular cell types in tuber versus adjacent cortical tissue, which led us to hypothesize that alterations in the neurovascular unit could be an important contributor to cortical tuber pathology and progression. The goals of this research are to: A) understand the natural disease history of brain calcification in a cohort of TSC patients as it relates to intractable epilepsy, and B) leverage TSC patient-specific cell lines derived from brain biopsies to test how TSC1/TSC2 deficiency and calcification affects BBB integrity and function using an in vitro system of the BBB. An innovative aspect of this research is that potential mechanisms identified from in vitro studies using TSC patient samples could potentially be correlated with clinical imaging data and other clinical features from the same patient, thus bridging the gap between basic and clinical research. Though we have only established one Nationwide Children’s Hospital TSC patient with paired clinical/in vitro data, our long-term plan is to expand this research paradigm with a greater diversity of TSC patients. Importantly, these analyses will build on our preliminary data to provide a deeper characterization of brain calcification in TSC patients, while providing further insights into the molecular underpinnings of calcification and pericyte dysfunction on BBB integrity in TSC. In sum, we expect this research to provide a deeper understanding of the natural disease history of TSC regarding brain calcification and development of drug-resistant epilepsy, which will ultimately lead to the development of therapeutic options for patients. We envision this Exploration - Hypothesis Development Award mechanism will lead to larger studies aimed at discovering molecular targets for therapy development to slow or prevent cortical tuber calcification, which will ultimately benefit TSC patients with intractable epilepsy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110278
Entities
People
- Mark Hester
Organizations
- United States Army