Skin Manifestations of Tuberous Sclerosis

结节性硬化症的皮肤表现

• 批准号: 7035486
• 负责人: JACK L ARBISER
• 金额: $ 23.56万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-26 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035486
• 关键词: angiogenesis; athymic mouse; biological signal transduction; free radical oxygen; gene mutation; genetically modified animals; growth factor receptors; laboratory mouse; metalloendopeptidases; pathologic process; receptor expression; skin neoplasms; tuberous sclerosis; tumor suppressor proteins; vascular endothelial growth factors

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.

描述（由申请人提供）：皮肤硬化症的皮肤表现 本申请的重点是结节性硬化症（TS）的发病机制和相关的血管生成。脑硬化症是人类最常见的常染色体显性遗传疾病之一，发病率约为1/6000。因此，在美国，每天都有一个孩子出生时患有TS。在儿童时期，发病和死亡的主要原因是癫痫和智力迟钝，而随着年龄的增长，脑、肾和皮肤的良性和恶性肿瘤成为严重问题。两个基因已被发现是结节性硬化症的病因。第一个克隆的是tsd（hamartin），定位于9号染色体，第二个克隆的是tsc 2（tuberin），定位于16号染色体。虽然这种疾病中的一些病变表现出典型的肿瘤抑制基因杂合性丢失，但许多其他病变则没有。在这个建议中，我希望探索错构瘤形成的其他机制。这些机制包括显性突变的块茎蛋白，以及贡献的修饰基因的TS表型。 为了解决显性负突变的块茎蛋白，我的实验室已经创建了一个转基因小鼠模型，通过表达显性负块茎蛋白，类似于在人类TS中观察到的突变，后面的组成型启动子。有趣的是，这种转基因小鼠产生了一种独特的皮肤和脑错构瘤表型，以前在其他小鼠模型中没有观察到。我们还表明，这种显性负等位基因的tuberin（δ/ARG等位基因）异常激活akt和活性氧信号，这已经牵连在人类TS。因此，我们的模型使我们能够检查上游介质（受体酪氨酸激酶信号）和下游介质（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。 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： 具体目标1。确定TS相关细胞系是否表现出异常受体酪氨酸激酶信号传导。 具体目标2。通过显性负性信号转导基因和药物抑制来确定活性氧和akt通路的激活在TS皮损发病中的作用。 具体目标3。为了确定p16 ink 4a和PTCH（patched）的失调是否作为显性阴性表达tuberin转基因小鼠TS表型的修饰剂。