Tuberous sclerosis complex (TSC) is a developmental disorder characterized by tumor susceptibility in multiple organs, brain malformations, and neurological manifestations. Despite considerable progress in understanding the genetic and signaling mechanisms underlying the disease, effective treatments are still lacking, particularly with regard to the control of neurological symptoms. In this proposal, we plan to develop induced pluripotent stem cell (iPSC) lines from patient and unaffected siblings, and differentiate these cells to generate neuronal cultures as a novel in vitr system to identify cellular and molecular phenotypes of the disease. Since the patients carry identified, de novo, heterozygous mutations in the TSC2 gene, we will also attempt to correct the genetic TSC mutations in iPSCs using the TALEN technology. With these iPSC models at hand, we will determine whether heterozygous TSC2 neurons exhibit a morphological or synaptic phenotype. Second, we will determine whether they exhibit localized alterations in signal transduction complexes that are normally regulated by the TSC, such as mTORC1 and mTORC2. We hypothesize that heterozygous TSC2 neurons express a subtle morphological phenotype that results from the localized de-regulation of mTOR-containing signaling complexes. This phenotype may be key to the etiology of cognitive dysfunction and autism in TSC patients. TSC is a relatively rare disorder affecting approximately 1 in 6,000 individuals. However, it shares mechanistic underpinnings with a number of cortical malformation syndromes, and it is frequently associated with epilepsy (>90%), intellectual disability and autism (40-50%). Thus, our findings are relevant to the treatment of all these developmental brain disorders, extending the potential impact of our work beyond the field of TSC.

Public Health Relevance

Tuberous sclerosis complex (TSC) is a developmental disorder characterized by tumor susceptibility in multiple organs, brain malformations, and neurological manifestations. Despite considerable progress in understanding the genetic and signaling mechanisms underlying the disease, effective treatments are still lacking, particularly with regard to the control of neurological symptoms, which include epilepsy, intellectual disabilit and autism. TSC is caused by heterozygous mutations in TSC1 or TSC2 genes, which may affect the maturation of brain cells and the biochemical activity of the mTOR kinase. Understanding how these genes disrupt cellular function will lead to a better treatment for the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS089441-01
Application #
8790825
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (02))
Program Officer
Mamounas, Laura
Project Start
2014-09-30
Project End
2016-06-30
Budget Start
2014-09-30
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$229,322
Indirect Cost
$79,322
Name
Rutgers University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901