The continuing theme of this Neurogenetics Center is to elucidate the molecular etiology and to modify the course of hereditary neurologic diseases in humans. The current goals are: to determine the function of genes responsible for the hereditary neuroplasias - neurofibromatosis type 1 (NF1) and 2 (NF2), and tuberous sclerosis type 1 (TSC1) and 2 (TSC2), and to develop improved means of gene delivery to cells in the nervous system. These studies will also provide basic information on development and signaling mechanisms in the nervous system. PI Gusella - Characterization of Merlin Expression. The distribution and function of the NF2 gene product, merlin, will be evaluated in normal cells, including proliferating and differentiated Schwann cells, and in schwannoma and meningioma tumors using genetic, biochemical and immunologic methods. PI Ramesh, Co-investigators Haines and Short - Molecular Genetics of TSC2. Genetic analysis will be undertaken to resolve the roles of the TSC1 and TSC2 genes in tuberous sclerosis. This will involve detailed mutational analysis of the TSC2 gene (and the TSC1 gene when it becomes available), as well as immunochemical and biochemical resolution of the cellular distribution of the TSC2 protein, tuberin, and its interaction with other proteins in normal and tumor tissue. PI Buckler - Cloning and Characterization of the TSC1 Gene. Molecular genetic studies will be undertaken to identify the TSC1 gene. Once it is identified, RNA analyses and immunocytochemical and biochemical studies will be undertaken to elucidate its expression and function. PI Breakefield - Gene Delivery to the Nervous System. New modes of delivery will be developed using virus vectors to achieve more widespread and stable gene delivery to the nervous system. In one scheme, retrovirus vectors will be used in combination with migratory astrocytic lines; and in another scheme, amplicon and recombinant herpes simplex virus-derived vectors will be generated to allow limited replication in glia-derived cells, to promote latency in neurons, and to reduce toxic functions. This project will also generate retrovirus vectors for functional analysis of the NF2 and TSC gene products and will explore the role of the NF1 gene in neurofibroma formation by Schwann cells. These projects will be supported by Cores Tissue Culture, Linkage Analysis and Database Core (PI Haines), and Neuropathology (PI Louis, Co-investigator Short). Collectively these studies provide a continuum of research on hereditary human neurologic diseases from positional cloning of disease genes to functional analysis of the gene products to gene therapy, with an emphasis on disrupted growth regulation and signalling mechanisms in the phakomatoses.
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| 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 |
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| van Eeghen, Agnies M; Terán, Laura Ortiz; Johnson, Jason et al. (2013) The neuroanatomical phenotype of tuberous sclerosis complex: focus on radial migration lines. Neuroradiology 55:1007-1014 |
| 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 |
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