Role of CTGF in White Matter Development in Tuberous Sclerosis

Principal Investigator: SAHIN, MUSTAFA
Institution Receiving Award: CHILDREN'S HOSPITAL, BOSTON
Program: TSCRP
Proposal Number: TS120087
Award Number: W81XWH-13-1-0040
Funding Mechanism: Idea Development Award
Partnering Awards:
Award Amount: $739,505.00


Patients with tuberous sclerosis complex (TSC) are known to suffer from autism, intellectual disability, and epilepsy. Currently, there is no safe and proven cure for these neurological symptoms. Growing evidence suggests that patients with TSC have, in addition to the cortical tubers, other abnormalities that contribute to the neurological profile of this disease. Importantly, neurological symptoms may occur due to abnormal wiring of the neurons in individuals with TSC. One of the ways such wiring deficits arise is due to the abnormal development of myelin, a fatty insulation that dictates the speed and quality of the transmitted information between neurons. Recent advanced imaging studies indicate that this disrupted myelin formation is a key neurobiological factor in the intellectual deficits in TSC patients. Lack of proper myelination is also a salient finding in mouse models of TSC. In fact, rapamycin treatment of TSC knockout mice rescues this myelination defect and improves the neurological outcome of these mice. However, mTOR inhibitors can have significant side effects, such as chronic immunosuppression and associated risk of serious infections. In pediatric patients, mTOR inhibitors may cause impaired growth. Therefore, finding alternative targets that can improve neuronal wiring is of utmost importance. Our research has identified a protein that is secreted by TSC-deficient neurons and inhibits proper myelination. Blocking this protein appears sufficient for the myelination to improve. Based on these findings, we believe that this newly identified protein (known as CTGF) can be a treatment target for the neurological symptoms of TSC. This proposal will use advanced cell biology and genetic techniques to study how neurons connect in mouse models of TSC and how we can improve defects in the myelin. Better understanding of the way neuronal connectivity goes awry is essential to develop new therapies for TSC.