Skin Manifestations of Tuberous Sclerosis

描述(申请人提供)：结节性硬化症的皮肤表现 这一应用主要集中在结节性硬化症(TS)的发病机制和相关的血管生成。结节性硬化症是人类最常见的常染色体显性遗传病之一，在人群中的发病率为1/6000。因此，在美国，每天有一个孩子出生时就患有TS。在儿童时期，癫痫和智力低下是发病率和死亡率的主要原因，而随着年龄的增长，大脑、肾脏和皮肤的良性肿瘤和恶性肿瘤变得非常有问题。已发现两种基因是结节性硬化症的致病基因。第一个被克隆的是TSD(Hamartin)，定位于9号染色体；第二个是TSC2(Tuberin)，定位于16号染色体。虽然这种疾病的一些病变表现出典型的肿瘤抑制基因杂合性丢失，但许多其他病变没有。在这项提议中，我希望探索错构瘤形成的其他机制。这些机制包括结节蛋白的显性突变，以及修饰基因对TS表型的贡献。 为了解决tuberin中的显性负突变，我的实验室通过在构成启动子后面表达显性负tuberin，类似于在人类TS中观察到的突变，创建了一个转基因小鼠模型。有趣的是，这种转基因小鼠出现了以前在其他小鼠模型中没有观察到的皮肤和脑错构瘤的独特表型。我们还发现，Tuberin的这个显性负等位基因(Delta/ARG等位基因)异常地激活了AKT和活性氧信号，这两个信号与人类TS有关。因此，我们的模型允许我们检查上游介体(受体酪氨酸激酶信号)和下游介体(其他遗传事件)对固定遗传背景的影响。了解这些上游和下游事件如何影响TS表型可能会导致可以预防或改善TS表型和人类其他皮肤病的治疗方法。 假设：结节性硬化症的皮肤表现是由特定的信号异常引起的： 具体目的1.确定TS相关细胞系是否存在异常的受体酪氨酸激酶信号转导。 具体目的2.通过利用显性负信号转导基因和药物抑制，探讨活性氧激活和AKT通路在TS皮损发病机制中的作用。 具体目的3.确定p16INK4a和PTCH(Patted)的失调是否在表达显性阴性tuberin的转基因小鼠中作为TS表型的修饰者。

DESCRIPTION (provided by applicant): Skin Manifestations of Tuberous Sclerosis This application focuses on the mechanisms of pathogenesis of tuberous sclerosis (TS) and associated angiogenesis. Tuberous sclerosis is one of the most common autosomal dominant disorders in humans, occuring at a frequency of 1/6000 in the population. Thus, in the United States, one child is born every day with TS. In childhood, the major causes of morbidity and mortality are seizures and mental retardation, while with increasing age, benign and malignant tumors of the brain, kidney and skin become highly problematic. Two genes have been found to be causative for tuberous sclerosis. The first one cloned is tsd (hamartin), localized to chromosome 9, and the second one is tsc2 (tuberin), localized to chromosome 16. While some of the lesions in this disorder show the classic loss of heterozygosity for tumor suppressor genes, many other lesions do not. In this proposal, I wish to explore other mechanisms of hamartoma formation. These mechanisms include dominant mutations in tuberin, as well as contribution of modifying genes to the TS phenotype. In order to address dominant negative mutations in tuberin, my laboratory has created a transgenic mouse model by expressing a dominant negative tuberin, analogous to mutations observed in human TS, behind a constitutive promoter. Interestingly, this transgenic mouse develops a unique phenotype of skin and brain hamartomas not previously observed in other mouse models. We have also shown that this dominant negative allele of tuberin (delta/ARG allele) aberrantly activates akt and reactive oxygen signaling, which have been implicated in human TS. Thus, our model allows us to examine the effect of upstream mediators (receptor tyrosine kinase signaling) and downstream mediators (other genetic events) on a fixed genetic background. Knowledge of how these upstream and downstream events impact on the TS phenotype may lead to therapies that can prevent or ameliorate the phenotype of TS and other skin disorders in humans. Hypothesis: Cutaneous manifestations of tuberous sclerosis are caused by specific signaling abnormalities: Specific Aim 1. To determine whether TS-related cell lines demonstrate aberrant receptor tyrosine kinase signaling. Specific Aim 2. To determine the role of activation of reactive oxygen and akt pathways in pathogenesis of cutaneous lesions of TS through the use of dominant negative signal transduction genes and pharmacologic inhibition. Specific Aim 3. To determine whether dysregulation of p16ink4a and PTCH (patched) acts as a modifier of theTS phenotype in transgenic mice expressing dominant negative tuberin.