Project 1- Molecular genetics of meningioma and NF-related disorders Meningiomas are brain tumors arising from the arachnoidal cells of the meninges that may occur sporadically, or in association with the inherited disorder, neurofibromatosis 2 (NF2). They account for about 25% of brain tumors and cause significant morbidity. A little more than half of sporadic meningiomas are caused by loss of merlin, the NF2 tumor suppressor protein, while the remainder is due to unknown causes.. As part of this Program Project grant, in 1993, we successfully isolated the NF2 gene and subsequently, we developed the reagents necessary to analyze merlin function and performed a basic characterization of merlin's structure and expression, finding that virtually all germline and somatic NF2 mutations involve elimination of merlin protein expression. In the past grant period, we focused on an examination of genetic changes in the initiation and progression of meningioma, using both merlin(-) and merlin(+) tumor specimens, and on the effects of these changes on cultured meningioma cells compared with their wild-type arachnoidal cell counterparts. In the coming grant period we plan to employ what we have learned in both genetic and cell biological studies to 1) identify and characterize genes involved in initiating meningioma tumor formation;2) identify and characterize genes involved in progression of these tumors to a more aggressive state;and 3) extend the strategy of whole genome analysis using array comparative genomic hybridization to other tumors from related disorders, including a) comparing pain-associated schwannomas from schwannomatosis to the schwannomas without associated pain seen in NF2 patients;b) comparing sporadic angiomyolipomas with angiomyolipomas found in association with tuberous sclerosis and c) performing an initial assessment of chromosomal changes in the periungual fibromas of tuberous sclerosis. Our findings from the previous grant period suggest that genetic changes can be a useful diagnostic tool in distinguishing different types of meningiomas that have very different prognosis for the patient. Thus, our investigations are likely to have a direct impact on improving diagnostic certainty and classification of meningiomas and result in better management of patients with these tumors. However, the longer-term impact will be the discovery of the specific molecular mechanisms that cause tumor growth and, by consequence, the delineation of targets against which new, specific therapeutic drugs can be developed to prevent the enlargement or recurrence of meningiomas and the morbidity and mortality that they cause.
| 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 |
| 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 |
| Boronat, Susana; Van Eeghen, Agnies M; Shinnick, Julianna E et al. (2013) Stressor-related disorders in tuberous sclerosis. Ann Clin Psychiatry 25:243-9 |
| 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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