Tuberous sclerosis (TSC) is an autosomal dominant tumor suppressor gene syndrome, characterized by development of distinctive benign tumors (hamartomas) and malformations (hamartias) in multiple organ systems. The brain lesions (cortical tubers, subependymal nodules, and cerebral white matter migration tracts) account for the most severe manifestations in most patients, including seizures, mental retardation, and autism and other developmental disorders. The long-term objective of this project is to develop and analyze authentic brain models ofTSC in the mouse, so that we can better understand the pathogenesis of TSC in the brain and develop effective therapeutic approaches. We have created a floxed Tsc1 conditional allele, which is a critical reagent for this study. In the first aim, we will complete an analysis of mice in which we have engineered complete loss of Tsc1 in the majority of cortical and hippocampal neurons. These mice are severely affected with both spontaneous and inducible seizure activity, a neurologic wasting syndrome, with ectopic and dysplastic neurons in both the cortex and hippocampus, and a myelination defect;all without genetic modification of astrocytes or astrogliosis. This model displays a marked therapeutic response to rapamycin/RADOOl treatment with increase in median survival from 35d to >100d. We will examine cortical layer organization through use of specific antibodies and BrdU birthdating, assess neurotransmitter-receptor and transcription factor expression alterations, and assess the response to interrupted rapamycin/RADOOl treatment in this model. In the second aim, we will explore a second brain model of TSC, using a regulable neural progenitor cell specific promoter in the form of the rtTA-tet-on system. Detailed studies of cortical development, seizure predilection, and response to rapamycin/RADOOl will be performed. In the third aim, we will explore the specificity of a set of novel brain enhancers for the cortex, and select one or more of them for use in generating a novel .inducible brain model of TSC, using the ere recombinase-estrogen receptor (Cre-ER) system. Through these approaches, we will be able to modulate the amount of recombination in neural progenitor cells, leading to variable fractions of cells lacking Tsc1 during various stages of brain development.
| Jordan, Justin T; Smith, Miriam J; Walker, James A et al. (2018) Pain correlates with germline mutation in schwannomatosis. Medicine (Baltimore) 97:e9717 |
| Prabhakar, Shilpa; Zhang, Xuan; Goto, June et al. (2015) Survival benefit and phenotypic improvement by hamartin gene therapy in a tuberous sclerosis mouse brain model. Neurobiol Dis 82:22-31 |
| Geffrey, Alexandra L; Shinnick, Julianna E; Staley, Brigid A et al. (2014) Lymphedema in tuberous sclerosis complex. Am J Med Genet A 164A:1438-42 |
| Boronat, Susana; Shaaya, Elias A; Auladell, Maria et al. (2014) Intracranial arteriopathy in tuberous sclerosis complex. J Child Neurol 29:912-9 |
| Di Nardo, Alessia; Wertz, Mary H; Kwiatkowski, Erica et al. (2014) Neuronal Tsc1/2 complex controls autophagy through AMPK-dependent regulation of ULK1. Hum Mol Genet 23:3865-74 |
| Prabhakar, Shilpa; Taherian, Mehran; Gianni, Davide et al. (2013) Regression of schwannomas induced by adeno-associated virus-mediated delivery of caspase-1. Hum Gene Ther 24:152-62 |
| Hsieh, David T; Jennesson, Melanie M; Thiele, Elizabeth A (2013) Epileptic spasms in tuberous sclerosis complex. Epilepsy Res 106:200-10 |
| van Eeghen, Agnies M; Pulsifer, Margaret B; Merker, Vanessa L et al. (2013) Understanding relationships between autism, intelligence, and epilepsy: a cross-disorder approach. Dev Med Child Neurol 55:146-53 |
| Prabhakar, Shilpa; Goto, June; Zhang, Xuan et al. (2013) Stochastic model of Tsc1 lesions in mouse brain. PLoS One 8:e64224 |
| Shaaya, Elias A; Hirshberg, Jacqueline S; Rabe, Olivia T et al. (2013) Cardiac fat-containing lesions are common in tuberous sclerosis complex. Am J Med Genet A 161A:1662-5 |
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