Skin Manifestations of Tuberous Sclerosis

结节性硬化症的皮肤表现

基本信息

批准号：
7674820
负责人：
JACK L ARBISER
金额：
$ 21.89万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-26 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7674820
关键词：
Address Adult Age Alleles Angiofibroma Angiogenesis Inhibitors Basal Cell Nevus Syndrome Benign Brain Brain Hamartoma Brain Neoplasms CDKN2A gene Cell Line Cell model Cells Child Childhood Chromosomes, Human, Pair 16 Chromosomes, Human, Pair 9 Cutaneous Data Development Disease Doctor of Medicine Doctor of Philosophy Dominant-Negative Mutation Event Exhibits Frequencies Gene-Modified Genes Genetic Genotype Giant Cells Growth Hamartoma Hemorrhage Human Hypersensitivity In Vitro Kidney Kidney Failure Kidney Neoplasms Knowledge Laboratories Lead Lesion Life Loss of Heterozygosity Malignant Neoplasms Malignant neoplasm of brain Matrix Metalloproteinases Mediator of activation protein Mental Retardation Modeling Morbidity - disease rate Mus Mutation NIH 3T3 Cells Neoplasms Neurofibromatoses Other Genetics Oxygen PTCH gene Pain Pathogenesis Pathway interactions Patients Phenotype Platelet Factor 4 Platelet-Derived Growth Factor Point Mutation Population Principal Investigator Protein Tyrosine Kinase Receptor Protein-Tyrosine Kinases Research Personnel Role Sclerosis Seizures Signal Pathway Signal Transduction Signal Transduction Pathway Skin Skin Manifestations Structure Syndrome System Testing Tissues Transduction Gene Transgenic Mice Tuberous Sclerosis Tumor Suppressor Genes Tumor Suppressor Proteins Tyrosine Kinase Inhibitor United States Vascular Endothelial Growth Factors angiogenesis drug candidate human TSC1 protein human TSC2 protein in vivo inhibitor/antagonist insight migration mortality mouse model mutant novel therapeutic intervention overexpression prevent programs promoter receptor-mediated signaling relating to nervous system skin disorder skin lesion small molecule tumor tumor progression

项目摘要

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）：结节硬化症的皮肤表现该应用着重于结节硬化症（TS）和相关血管生成的发病机理。结节性硬化是人类最常见的常染色体显性疾病之一，发生在人群中的频率为1/6000。因此，在美国，一个孩子每天都有TS出生。在童年时期，发病率和死亡率的主要原因是癫痫发作和智力低下，而随着年龄的增长，脑，肾脏，肾脏和皮肤的良性和恶性肿瘤的增长变得非常有问题。已经发现两个基因对于结节性硬化是病因。第一个克隆的是TSD（Hamartin），位于9号染色体，第二个是TSC2（Tuberin），该疾病中的某些损伤表明，肿瘤基因的经典丧失肿瘤基因，许多其他病变却没有。在此提案中，我希望探索Hamartoma形成的其他机制。这些机制包括结核素中的主要突变，以及修饰基因对TS表型的贡献。为了解决TUBERIN中的主要负突变，我的实验室通过表达了主导性Tuberin，创建了一个转基因小鼠模型，该模型类似于人类TS中观察到的突变，在本构启动子之后。有趣的是，这种转基因小鼠发展了以前在其他小鼠模型中未观察到的皮肤和脑瘤的独特表型。我们还表明，Tuberin（Delta/arg等位基因）的这种主要负等位基因异常激活Akt和活性氧信号，这与人类TS有关。因此，我们的模型使我们能够检查上游介体（受体酪氨酸激酶信号传导）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对TS表型的影响如何导致疗法可以预防或改善人类TS和其他皮肤疾病的表型。假设：结节硬化症的皮肤表现是由特定信号异常引起的：具体目标1。确定与TS相关的细胞系是否表现出异常的受体酪氨酸激酶信号传导。具体目的2。通过使用主要的负阴性信号转导基因和药理抑制作用，为了确定活性氧和AKT途径在TS皮肤病变的发病机理中的活化作用。具体目的3。确定p16Ink4a和PTCH（修补）的失调是否充当表达显性阴性Tuberin的转基因小鼠的Thets表型的修饰符。