Tuberous Sclerosis: Mutations and Murine Models

结节性硬化症(TSC)是一种常染色体显性肿瘤抑制基因综合征，每6,000人中就有1人受到影响 出生，以发展为独特的良性肿瘤(错构瘤)和畸形为特征 (甲藻)在多器官系统中。尽管皮质瘤是该病的最大致病原因 幼儿脑部错构瘤进行性生长(室管膜下巨细胞星形细胞瘤)， 肾(血管肌脂瘤)和肺(淋巴管肌瘤病)在#年的临床影响最严重。 年龄较大的儿童、青少年和成年人。有两个基因引起TSC：TSC1和TSC2，每个基因都维持 通过两次击打的肿瘤抑制基因导致疾病发病机制的失活突变 机制存在于大多数组织中。最近的研究强调了某些错义突变的关联 具有变异型TSC样病表型的TSC2。我们建议在患者和小鼠模型上进行研究。 探讨TSC及其相关的TSC样疾病的发病机制。首先，我们将检查切除的 室管膜下巨细胞星形细胞瘤、血管脂肪瘤和淋巴管肌瘤病 导致疾病进展的变化。我们假设额外的遗传事件超出了 二次打击发生在这些病变中的一小部分，这些病变逐渐生长。第二，我们将执行一项 利用睡美人在我们的Tsc2小鼠模型中筛选促进肿瘤发生的遗传事件 转座子。第三，我们将在TSC2中开发敲入错义突变，以匹配在变体TSC中看到的错义突变 研究杂合子和纯合子小鼠的发育事件，以及信号和 在其衍生组织和细胞系中的分化效应。第四，我们将开发一种小鼠模型 合并TSC2-PKD1缺失综合征，表现为加速性多囊肾病。这款车 将允许分析在肾囊肿发病过程中发生的遗传和信号事件。

Tuberous sclerosis (TSC) is an autosomal dominant tumor suppressor gene syndrome affecting 1 in 6,000 births, characterized by development of distinctive benign tumors (hamartomas) and malformations (hamartias) in multiple organ systems. Although cortical tubers cause the greatest morbidity of the disease in young children, progressive growth of hamartomas in the brain (subependymal giant cell astrocytomas), kidney (angiomyolipomas), and lung (lymphangioleiomyomatosis) have the most severe clinical impact in older children, adolescents, and adults. Two genes cause TSC: TSC1 and TSC2, each of which sustains inactivating mutations that lead to disease pathogenesis through a two hit, tumor suppressor gene mechanism in most tissues. Recent studies have highlighted the association of certain missense mutations in TSC2 with a variant TSC-like disease phenotype. We propose studies in both patients and mouse models to explore the pathogenesis of TSC and this related TSC-like disorder. First, we will examine resected subependymal giant cell astrocytomas, angiomyolipomas, and lymphangioleiomyomatosis for genetic changes that account for disease progression. We hypothesize that additional genetic events beyond the second hit occur in the small fraction of these lesions which progressively grow. Second, we will perform a screen for genetic events that enhance tumorigenesis in ourTsc2 mouse model, using the Sleeping Beauty transposon. Third, we will develop knock-in missense mutations in Tsc2 to match those seen in variant TSC families, to examine developmental events in heterozygous and homozygous mice, and signaling and differentiation effects in their derivative tissues and cell lines. Fourth, we will develop a mouse model of the combined Tsc2-Pkd1 deletion syndrome, in which accelerated polycystic kidney disease is seen. This model will permit analysis of genetic and signaling events occurring during renal cyst pathogenesis.