Intercellular Communiation in the Eye Lens

描述(申请人提供)：缝隙连接已知对于眼晶状体的生存和代谢稳态是必不可少的。我们和其他人一样，揭示了晶状体连接蛋白的一个新特征，它参与促进上皮纤维分化和晶状体发育。我们的长期目标是了解连接蛋白分子在晶状体发育和动态平衡中的分子机制(S)和功能意义。这项应用的目的是了解CX50在细胞分化和晶状体生长发育中的作用机制。核心假设是：(1)CX50通过与细胞周期调节因子相互作用参与晶状体的分化，这种作用独立于缝隙连接；(2)MIP促进了CX50在晶状体纤维中的定位和稳定。将追求两个具体目标：1)。明确CX50的PEST结构域在上皮纤维分化和晶状体发育中的分子机制。2)。确定MIP与CX50相互作用的功能意义。本研究的创新之处之一在于，本研究旨在剖析晶状体连接蛋白非常规功能的分子机制。此外，研究计划将使用我们建立的禽类逆转录病毒方法作为主要工具，用于原代鸡晶状体培养和活体鸡晶状体的实验操作。更重要的是，用野生型和基因敲除小鼠模型进行的拟议研究将验证和补充从小鸡晶状体中获得的发现。我们期望我们的实验结果将为理解CX50在晶状体纤维分化中的功能意义和调控机制提供分子基础，并有望对定义晶状体连接蛋白参与晶状体生长发育的过程产生重大的积极影响。我们的研究结果将是重要的，因为新发现的知识将有助于更广泛地理解上皮纤维分化和晶状体发育的机制方面。与公共卫生相关：白内障是最常见的眼病之一，也是全世界致盲的主要原因之一。拟议的研究活动将有助于了解晶状体功能和形成的生物学过程，从长远来看，应该对白内障的治疗策略做出新的贡献，并为药物发现和开发的新思路和潜在靶点做出新的贡献。

DESCRIPTION (provided by applicant): Gap junctions are known to be essential for the survival and metabolic homeostasis of the eye lens. We as well as others have revealed a novel feature of the lens connexin involved in promoting epithelial-fiber differentiation and lens development. Our long-range goal is to understand the molecular mechanism(s) and functional significance of connexin molecules in lens development and homeostasis. The objective of this application is to understand the mechanistic roles of Cx50 in cell differentiation, and in lens growth and development. The central hypothesis are: (1) Cx50 is functionally involved in lens differentiation by interacting with cell cycle regulators, a role independent of gap junctions; (2) the localization and stabilization of Cx50 in lens fibers is facilitated by MIP. Two specific aims will be pursued: 1). Define the molecular mechanism of the PEST domain of Cx50 in epithelial-fiber differentiation and lens development. 2). Determine the functional significance of the interaction of MIP and Cx50. One of the innovative aspects is that this proposal aims to dissect the molecular mechanisms of an unconventional function of lens connexin. Moreover, the research program will be accomplished using our established avian retroviral approaches as the principal tool for experimental manipulations of primary chick lens cultures as well as in vivo chick lenses. More importantly, the findings obtained from chick lens will be validated and complemented by proposed studies using wild type and knockout mouse models. It is our expectation that our experimental findings will provide a molecular basis for understanding the functional significance and regulatory mechanisms of Cx50 in differentiating lens fibers and are expected to have a major positive impact on defining the process by which lens connexins are involved in lens growth and development. The outcomes of our research will be significant because the new knowledge discovered will contribute to a broader understanding of mechanistic aspects of epithelial-fiber differentiation and lens development. Public health relevance: Cataracts are one of the most common eye diseases and also one of the leading causes for blindness worldwide. The proposed research activity will help understanding the biological process of lens function and formation and, in a long run, should make novel contributions to strategies for treatment of cataracts, and to new ideas and potential targets for drug discovery and development.