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Molecular Genetics of Inherited Neurological Diseases


The goals of this Neurogenetics Center are to understand the molecular/cellular etiology and to ameliorate the course of the hereditary phakomatoses, neurofibromatosis type 2 (NF2), tuberous sclerosis (TSC) and related disorders. NF2 schwannomas can cause deafness, pain and paralysis, and meningiomas result in brain compression and occlusion of major sinuses, which are life threatening. TSC has severe manifestations including seizures, mental retardation and autism. These neurofunctional diseases share features of disrupted signaling pathways leading to abnormal neural cell development and growth due to loss of function of tumor suppressor genes. The focus of the proposed studies is on understanding genetic and cellular factors contributing to formation and progression of tumors, as well as disruption of neural development, and on generating mouse models which will allow assessment of therapeutic strategies. Project 1 (Gusella/Ramesh) - Molecular genetics of meningioma and NF-related disorders: identify additional genes and signaling pathways involved in initiation and progression of meningioma, schwannoma and related tumors, including schwannomas in schwannomatosis, and angiomyolipomas and subungual fibromas in TSC, and the role of associated proteins in cytoskeletal dynamics and abnormalities in target cells; Project 2 (Kwiatkowski) - Mouse brain models of tuberous sclerosis: create and analyze authentic brain models of TSC in conditional Tsc1 knock-out mice to gain a detailed understanding of developmental events contributing to these lesions, including role of neuroprecursor cells and response to rapamycin therapy. Project 3 (Breakefield/Sena-Esteves) - Vector query and therapy for NF2 and TSC lesions: use viral vectors to evaluate the contribution of different Tsc1-null cell types to abnormal development of the brain and to rescue a Tsc1-null neurologic phenotype by gene replacement. MicroRNA profiling of meningioma will be used to elucidate changes in concert with genomic and mRNA analyses in Project 1. Mouse models of schwannomas will be used to investigate ontogeny and treatment. These projects will be supported by Cores for Administration (Breakefield), Clinical co-ordination (Thiele/Plotkin) including clinical assessment, databases and genotype/phenotype correlations and Neuropathology and tumor banking (Stemmer-Rachamimov/Louis) ensuring reliable collection and neuropathologic assessment of human and mouse tumor/tissue samples. These cores provide a major strength to the Center in coordinating basic research and clinical investigation to facilitate translation to patient care. Collectively these studies provide a concerted effort toward understanding the genes, proteins and cells that contribute to associated tumors and malformations in the nervous system underlying neurologic deficits in NF2 and TSC for the purposes of more effective diagnosis and development of treatment paradigms.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.