In both tuberous sclerosis (TSC) and neurofibromatosis type 2 (NF2) loss of gene function alters the development of the nervous system, resulting in abnormal structures and benign tumors. In the case of TSC, the target cells are thought to be neuroprecursor cells (NPCs), astrocytes and young neurons, and in the case of NF2, Schwann cells in peripheral nerves, as well as arachnoidal cells in the brain. Adeno-associated virus (AAV) will be used to elucidate cells of origin and create mouse models of brain lesions in TSC and schwannomas in NF2;both AAV and herpes simplex virus (HSV) amplicon vectors will be used to explore treatment paradigms for these lesions.
Aim 1 a is directed towards determining the contribution of NPCs to brain lesions in a mouse model of TSC. Mice homozygous for both conditional, Tsc1 knock-out and lacZ knock-on alleles will receive intracranial ventricular (ICV) injections of AAV vectors bearing Cre recombinase under NPC and constitutive promoters at different times in brain development. The fate of Tsc1 null/lacZ+ cells will be evaluated to determine their contribution to enlarged neurons, multi-lineage phenotypes, and proliferative foci in the brain.
In Aim 1 b we will evaluate the ability of AAV vectors encoding hamartin to correct the neurologic phenotype of Tsct dc x synapsin-1-Cre offspring following injection into the developing brain as compared to rapamycin treatment. Mice will be monitored for neuroanatomical features, as well as weight gain, seizures and age of death.
Aim 2 is directed towards identifying disregulated microRNAs in human meningioma tumors relative to merlin status and to normal cells of origin. Correlations will be made with clinical status, neuropathology, genomic changes and mRNA levels. Validated microRNA and mRNA changes will be evaluated for effects on growth of meningioma cells and tumors.
Aim 3 is designed to develop a model for spontaneous Nf2-null schwannomas using conditional Nf2 knock-out mice and AAV Cre vectors in a nerve injury model, including evaluation of role of p53 status and monitoring by bioluminescence imaging. In addition we will evaluate the ability of HSV amplicon vectors expressing an apoptotic protein to achieve regression of implanted (and spontaneous) human schwannoma tumors. These studies will inform therapeutic strategies in two ways: first, by elucidating the specific neural cell types, conditions and time at which different types of lesions form in the Tsc1-null and NF2-null cells in the nervous system, and second, by evaluating the ability of gene replacement to rescue Tsc1-null neurons and extend lifespan, and to """"""""debulk"""""""" schwannoma tumors while sparing neurons.
|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|
Showing the most recent 10 out of 261 publications