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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.