MURINE MODELS OF TSC1: MECHANISMS AND THERAPIES

Massachusetts General Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): Tuberous sclerosis complex (TSC1s an autosomal dominant genetic disease affecting 1 in 6,00 births, that is characterized by benign tumors (hamartomas and hamartias) in multiple organ systems. Its major clinical manifestations are due to brain involvement-seizures, mental retardation, and autism and related disorders, each of which occur in about half of TSC patients. Two genes (TSC1 and TSC2) cause this disorder and both have recently been identified. We propose a series of studies using the mouse as a model system to study the pathogenesis and therapy of TSC due to mutations in TSC1. First, we have created a conventional Tsc1 knock-out mouse, and will define the viability of the Tsc1 null state, the phenotype and tumor predisposition of the heterozygotes, and the cell culture characteristics of primary cell lines that are Tsc1 null obtained from these mice. Second, we have also generated a conditional 'Floxed' Tsc1 allele. Through breeding of these animals with tissue specific cre recombinase expressing animals, we will obtain organ-specific Tsc1 null mice to explore the pathogenesis of brain, cardiac, and renal disease in these animals. Direct organ or vascular injection of viral vectors encoding cre will also enable generation of regional Tsc1 knock-outs. Through use of both of these techniques, we will be able to determine the cells involved in and developmental course of Tsc1 lesion development. Primary cells will also be obtained from several sites in these animals, and subjected to cre expression in culture to assess the effects of Tsc1 loss. We will also explore gene therapy approaches to brain lesion control in these mice. Last, we will examine the consequences of expression of missense mutations in TSC1 in both cultured cells and in the mouse, to examine a dominant negative effect hypothesis; and delete a putative Tsc1 locus control region element in the mouse.