Intercellular communication in the lens

晶状体中的细胞间通讯

• 批准号: 8301710
• 负责人: Miduturu Srinivas
• 金额: $ 33.59万
• 依托单位: STATE COLLEGE OF OPTOMETRY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301710
• 关键词: Age; Age of Onset; Aging; Antioxidants; Biochemical; Biological Assay; Blindness; Cataract; Cell Aging; Cell Nucleus; Cells; Collaborations; Communication; Connexin 43; Connexins; Coupling; Crystallins; Cysteine; Diabetes Mellitus; Diffusion; Disease; Enzymes; Epithelium; Fiber; Gap Junctions; Gene Deletion; Genes; Glutathione; Growth; Human; In Vitro; Knock-out; Laboratories; Lead; Lens Fiber; Link; Maintenance; Measures; Mediating; Methionine; Methods; Modification; Molecular; Mus; Mutation; Oxidants; Oxidative Stress; Oxides; Pathway interactions; Permeability; Post-Translational Protein Processing; Principal Investigator; Property; Proteins; Relative (related person); Role; Senile Cataract; System; Techniques; Transgenic Mice; Universities; abstracting; age effect; age related; base; catalase; cell age; congenital cataract; fiber cell; gap junction channel; in vivo; inhibitor/antagonist; intercellular communication; lens; lens gap junction; lens protein; middle age; oxidation; oxidative damage; postnatal; regional difference

Abstract Gap junctional communication provided by connexin channels is required for postnatal lens growth and transparency. Targeted deletions of genes encoding Cx46 and Cx50 lead to cataracts in mice. Similarly, mutations in both Cx50 and Cx46 genes cause a variety of cataract types in both humans and mice. Alterations in coupling have been suggested to underlie cataracts that occur with diabetes and with age, but there are few studies directly linking gap junctional coupling to these pathophysiological conditions. More recently, we found that there are differences in the molecular permeability through channels made of Cx46, Cx50 and Cx43. In this proposal, we will continue to pursue electrophysiological studies to understand how the diversity in channel types formed by connexin proteins influences lens function and how their alteration leads to congenital and age-related cataracts by pursuing the following two Aims. In Aim 1, we will determine the importance of coupling provided by Cx46 and Cx50 gap junctions in the lens in the maintenance of adequate concentrations of important metabolites in inner fiber cells. We will use electrophysiological and biochemical assays to study the permeation of molecules in vitro and in vivo. We will also determine whether Cx50 and Cx46 mutations that cause congenital cataracts have alterations in molecular permeability. Second, we will determine whether coupling conductance and/or permeability is altered with aging and oxidative stress. Mass spectrometric methods will be employed to identify modifications to connexins with aging and during cataractogenesis. The effect of modifications on conductance and permeability of gap junctions will be assessed using electrophysiological methods.

摘要