Molecular Genetics of Inherited Neurological Diseases

Massachusetts General Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant) The goals of this Neurogenetics Center are to elucidate the molecular etiology and to ameliorate the course of hereditary tumors of the nervous system, in particular in neurofibromatosis type 2 (NF2) and tuberous sclerosis (TSC) This research will provide insight into the etiology of spontaneous neural tumors and mechanisms of growth regulation in the developing nervous system. The focus of the proposed studies is on understanding the genetic basis of functional changes in merlin (NF2), hamartin (TSC1) and tuberin (TSC2) and their role in formation and progression of meningiomas and other brain tumors. Elucidation of the cellular function of these proteins will be facilitated through identification and characterization of interacting proteins. Further, transgenic mouse models of these diseases will be used to understand physiologic changes associated with loss of these tumor suppressor genes and to provide a platform for therapeutic strategies. Project 10 (Gusella)-Molecular genetics of meningioma and NF-related disorders: elucidate cellular functions of merlin in growth and adhesion; determine the role of this and other genes in the ontogeny and progression of meningiomas; and identify genes involved in related, hereditary neural tumor syndromes; Project 11 (Ramesh, Ito)-Characterization of TSC proteins hamartin and tuberin: determine whether cortical lesions in TSC patients have loss of heterozygosity at the cellular level; and characterize the role of tuberin in control of cell cycle via elucidation of interacting proteins in mammalian cells and Drosophila; Project 12 (Kwiatkowski)-Murine models of TSC1: mechanisms and therapies: generate and characterize knock-out and conditional transgenic mice for TSC1 in the homozygous and heterozygous states and in different genetic backgrounds; characterize the phenotypic consequences of missense mutations in TSC1; and attempt to arrest cell growth in lesions using vectors. Project 13 (Breakefield, Brown)-Gene therapy for hereditary tumors in experimental models of TSC: evaluate gene delivery in mouse models of liver hemangioma, cortical harmartomas and renal cell carcinoma (TSC2+/-); generate brain lesions in TSC1 conditional knock-out animals by injection of Cre-bearing vectors; and test gene therapy models in vivo with herpes hybrid amplicon vectors and endothelial cell vehicles bearing genes for anti-angiogenic and apoptotic factors. These projects will be supported by Cores for Clinical Services (Sims, MacCollin) and Neuropathology and Tumor Banking (Louis and Stemmer-Rachamimov). Collectively these studies provide a concerted effort towards understanding the neurologic functions of NF2 and TSC genes and treating disease manifestations associated with these diseases.