Cx26 mutations in syndromic deafness linked to skin disease

与皮肤病相关的综合征性耳聋中的 Cx26 突变

基本信息

批准号：
7861467
负责人：
THOMAS W WHITE
金额：
$ 36.41万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7861467
关键词：
Alleles Amino Acids Animal Model Animals Antisense Oligonucleotides Behavior Biological Assay Cell Culture Techniques Cell Line Cells Connexins Cyclic AMP Data Disease Dyes Epidermis Exhibits Flufenamic Acid Gap Junctions Gel Genes Health Hearing Impaired Persons Homeostasis Human In Vitro Individual Intervention Ion Exchange Keratin Lead Link Mediating Membrane Methods Mus Mutation Palmoplantar Keratosis Pathology Permeability Pharmaceutical Preparations Pluronics Property Protein Subunits Proteins Publishing Second Messenger Systems Senter syndrome Skin Skin Abnormalities Syndrome System Terminator Codon Testing Tetanus Helper Peptide Tetracycline Control Therapeutic Therapeutic Intervention Topical application Trans-Activators Transgenes Transgenic Animals Transgenic Mice Xenopus oocyte deafness disease-causing mutation gain of function human disease in vivo inhibitor/antagonist insight keratinocyte loss of function loss of function mutation mouse model mutant novel promoter public health relevance second messenger skin disorder

项目摘要

DESCRIPTION (provided by applicant): Connexins are the subunit proteins of gap junctions, which allow the exchange of ions, second messengers and small metabolites between adjacent cells through intercellular channels. In addition, connexins can form functional hemichannels in non-junctional membranes. Mutations in connexin genes cause a variety of human diseases, including deafness and skin disorders. For example, mutations in connexin26 (Cx26, or GJB2) cause nonsyndromic deafness, or syndromic deafness associated with a variety of skin disorders including palmoplantar keratoderma (PPK), keratitis- ichthyosis-deafness syndrome (KID), and Vohwinkel syndrome (VS). The Cx26 mutations causing skin diseases and deafness are all single amino acid changes, and the mechanism(s) whereby they lead to skin pathology are unknown. Since nonsyndromic deafness is predominantly a loss of function disorder, it follows that the syndromic mutants may show an alteration, or gain, of function to cause skin disease. In this proposal, we seek to precisely define the functional consequences of Cx26 mutations that cause skin disease in humans. In addition, we seek to develop animal models that replicate human skin disorders caused by connexin mutations and use them to explore potential therapeutic intervention strategies. We propose first to examine the functional properties of dominant Cx26 mutations that cause skin disease. Second, we will generate transgenic mouse models of human skin disease and characterize the progression of epidermal pathology. Third, we will use pharmacological inhibition and/or antisense mediated knockdown in transfected cell systems and transgenic animals to inhibit mutant connexin activity. These studies will provided insights into how mutations alter the functional activity of Cx26 leading to skin disease, if these novel functions change epidermal homeostasis in animal models, and whether specific inhibition of the mutant proteins will show promise as a potential therapeutic strategy. PUBLIC HEALTH RELEVANCE: Mutations in connexin genes cause a broad spectrum of human health problems. In the case of Cx26, functional studies have revealed much about deafness causing mutations, but very little is known about the functional consequences of Cx26 mutations that cause skin disease. The proposed studies will show how mutations alter the functional activity of Cx26 leading to skin disease, whether these novel functions cause skin disease in experimental animals, and if specific inhibition of the mutant proteins will show promise as a possible therapeutic strategy.

描述（由申请人提供）：连接蛋白是间隙连接的亚基蛋白，可以通过细胞间通道在相邻细胞之间交换离子，第二信使和小型代谢物。另外，连接蛋白可以在非交连膜中形成功能性半通道。连接基因的突变会引起各种人类疾病，包括耳聋和皮肤疾病。例如，Connexin26（CX26或GJB2）中的突变引起非综合性耳聋或综合性耳聋，与包括多种皮肤疾病有关，包括掌状角膜疾病（PPK），角膜炎 - 肾小球 - ichthyosis-Deakiss-Deabness-Deafness-Deabndrome（KID）和Vohwinkel Syndrome（VS）。引起皮肤疾病和耳聋的CX26突变都是单个氨基酸的变化，并且它们导致皮肤病理的机制尚不清楚。由于非综合性耳聋主要是功能障碍的丧失，因此综合征突变体可能显示出引起皮肤疾病的功能的改变或增加。在此提案中，我们试图精确定义引起人类皮肤疾病的CX26突变的功能后果。此外，我们试图开发复制由连接蛋白突变引起的人类皮肤疾病的动物模型，并使用它们来探索潜在的治疗干预策略。我们首先建议检查引起皮肤疾病的主要CX26突变的功能性能。其次，我们将生成人类皮肤病的转基因小鼠模型，并表征表皮病理的进展。第三，我们将在转染的细胞系统和转基因动物中使用药理学抑制和/或反义介导的敲低来抑制突变的连接蛋白活性。这些研究将提供有关突变如何改变CX26导致皮肤病的功能活性的见解，如果这些新型功能改变了动物模型中的表皮稳态，以及对突变蛋白的特定抑制是否会表现出有望作为潜在的治疗策略。公共卫生相关性：连接蛋白基因的突变引起了各种各样的人类健康问题。在CX26的情况下，功能研究已经揭示了引起突变的耳聋，但对引起皮肤病的CX26突变的功能后果知之甚少。拟议的研究将显示突变如何改变CX26导致皮肤病的功能活性，这些新型功能是否导致了实验动物的皮肤疾病，以及对突变蛋白的特定抑制是否会显示出有望作为可能的治疗策略。