Skin Manifestations of Tuberous Sclerosis

结节性硬化症的皮肤表现

基本信息

批准号：
7278673
负责人：
JACK L ARBISER
金额：
$ 22.34万
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 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7278673
关键词：
Address Adult Age Alleles Angiofibroma Angiogenesis Inhibitors Appendix 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 Localized Loss of Heterozygosity Malignant Neoplasms Malignant neoplasm of brain Matrix Metalloproteinases Mediating 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 Pharmaceutical Preparations Phenotype Platelet Factor 4 Platelet-Derived Growth Factor Point Mutation Population Principal Investigator Protein Overexpression 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 Transgenic Organisms Tuberous Sclerosis Tumor Suppressor Genes Tumor Suppressor Proteins Tyrosine Kinase Inhibitor United States Vascular Endothelial Growth Factors angiogenesis day human TSC1 protein human TSC2 protein in vivo inhibitor/antagonist insight migration mortality mouse model mutant novel therapeutics prevent programs promoter receptor relating to nervous system skin disorder 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）：结节性硬化症的皮肤表现本申请重点研究结节性硬化症 (TS) 的发病机制和相关血管生成。结节性硬化症是人类最常见的常染色体显性遗传疾病之一，在人群中的发生频率为 1/6000。因此，在美国，每天都会有一名患有 TS 的孩子出生。在儿童时期，发病和死亡的主要原因是癫痫和智力低下，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。已发现两个基因与结节性硬化症有关。第一个克隆是 tsd（错构蛋白），位于 9 号染色体，第二个是 tsc2（马铃薯蛋白），位于 16 号染色体。虽然这种疾病中的一些病变表现出肿瘤抑制基因杂合性的典型损失，但许多其他病变则不然。在这个提案中，我希望探索错构瘤形成的其他机制。这些机制包括马铃薯蛋白的显性突变，以及修饰基因对 TS 表型的贡献。为了解决马铃薯球蛋白的显性失活突变问题，我的实验室通过在组成型启动子后面表达显性失活马铃薯球蛋白（类似于在人类 TS 中观察到的突变）创建了转基因小鼠模型。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，这是以前在其他小鼠模型中未观察到的。我们还表明，马铃薯蛋白的这种显性失活等位基因（δ/ARG 等位基因）异常激活 akt 和活性氧信号传导，这与人类 TS 有关。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传导）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 表型可能会带来预防或改善人类 TS 表型和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的受体酪氨酸激酶信号传导。具体目标 2. 通过使用显性负性信号转导基因和药物抑制来确定活性氧和 akt 途径的激活在 TS 皮肤病变发病机制中的作用。具体目标 3. 确定 p16ink4a 和 PTCH（修补）的失调是否充当表达显性失活马铃薯蛋白的转基因小鼠中 TS 表型的修饰剂。