Tuberous Sclerosis: Mutations and Murine Models

描述（由申请方提供）：动脉硬化症（TSC）是一种常染色体显性肿瘤抑制基因综合征，每6,000例新生儿中有1例受影响，其特征是在多器官系统中发生独特的良性肿瘤（错构瘤）和畸形（错构瘤）。虽然皮质结节在幼儿中引起的发病率最高，但在脑（室管膜下巨细胞星形细胞瘤）、肾（血管平滑肌脂肪瘤）和肺（淋巴管平滑肌瘤病）中进行性生长的错构瘤在年龄较大的儿童、青少年和成人中具有最严重的临床影响。两种基因导致TSC：TSC 1和TSC 2，它们中的每一个都维持失活突变，这些失活突变通过两次打击，在大多数组织中的肿瘤抑制基因机制导致疾病发病。最近的研究强调了TSC 2中某些错义突变与变体TSC样疾病表型的关联。我们建议在患者和小鼠模型中进行研究，以探讨TSC及其相关TSC样疾病的发病机制。首先，我们将检查室管膜下巨细胞星形细胞瘤、血管平滑肌脂肪瘤和淋巴管平滑肌瘤切除后引起疾病进展的基因改变。我们推测，在这些病变的一小部分中发生了超过第二次打击的额外遗传事件，这些病变逐渐生长。其次，我们将使用睡美人转座子在Tsc 2小鼠模型中筛选增强肿瘤发生的遗传事件。第三，我们将开发Tsc 2中的敲入错义突变，以匹配在变体TSC家族中观察到的那些，以检查杂合和纯合小鼠中的发育事件，以及它们的衍生组织和细胞系中的信号传导和分化效应。第四，我们将开发一种Tsc 2-Pkd 1缺失综合征的小鼠模型，其中可以看到加速的多囊肾病。该模型将允许分析肾囊肿发病过程中发生的遗传和信号事件。

DESCRIPTION (provided by applicant): 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 our Tsc2 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.