Understanding the Etiology of Tuberous Sclerosis Complex

Principal Investigator: BORDEY, ANGELIQUE
Institution Receiving Award: YALE UNIVERSITY
Program: TSCRP
Proposal Number: TS093067
Award Number: W81XWH-10-1-0041
Funding Mechanism: Idea Development Award
Partnering Awards:
Award Amount: $734,763.00


Tuberous Sclerosis Complex (TSC) is a genetic disorder that causes lesions in many different organs including the brain, skin, heart, kidney, and lungs. TSC is often first recognized by the associated skin lesions and neurological symptoms (i.e., seizures, mental retardation, autism, and hydrocephalus), which are the most significant causes of disability and morbidity. Currently, there are no known cures for TSC, and the etiology of the disease is not well understood. In TSC patients, mutations in one of two tumor suppressor genes, TSC1 or TSC2, result in the formation of lesions during perinatal life. TSC lesions, including cortical tubers and subependymal nodules, account for the associated neurological symptoms. However, TSC lesions have not been replicated in a mouse model, limiting our understanding of their etiology and tuber-associated seizure generation. Cortical tubers are thought to arise during late stages of embryonic development when individual neural progenitor cell generates neurons in a distinct cortical area. Defect in a single neural progenitor cell is thus expected to lead to the abnormal development of a patch of cortical neurons. In addition, the generation of brain cells persists beyond birth in the subependymal zone where subependymal nodules are generated.

Our objective is thus to test whether deletions of TSC genes in perinatal neural progenitors contribute to the generation of brain lesions and tuber-associated cortical hyperexcitability, and we propose to identify some of the mechanisms underlying that process. To achieve our goal, we will delete one of the TSC genes (i.e., Tsc1) selectively in neural progenitor cells using a novel approach in transgenic mice. We will first examine whether deletion of Tsc1 in perinatal progenitor cells generates cortical tubers and subependymal nodules. Second, we will examine whether the cortical regions surrounding the tubers display enhanced excitability. Finally, we will examine whether receptors for the neurotransmitter glutamate are overexpressed in cells with deleted Tsc1 (called Tsc1-null cells). We expect that Tsc1-null cells express glutamate receptors that are normally present only in immature cells and promote their proliferation and growth. Inhibiting the function of these receptors is expected to limit tuber growth as well as cortical excitability and seizure generation.

In conclusion, results from our work will provide important insights into the formation of TSC lesions and associated seizure symptoms. It is hoped that our novel technical approach will generate the first animal model of TSC that replicates the human pathology and can be used by others. Finally, our findings will aid in the design of new therapeutics to limit TSC lesion growth and the development of the associated neurological symptoms. Our search for new therapeutics is focused on selective glutamate receptors whose blockers can pass the blood brain barrier and enter the brain. Many of the glutamate receptor blockers are already approved for use in humans or are undergoing clinical trials. We thus expect that once we identify glutamate receptor blockers that limit tuber growth and associated cortical hyperexcitability, their clinical use can be accelerated and be approved in a couple of years.