Intercellular Communiation in the Eye Lens

描述（由申请人提供）：已知间隙连接对于眼透镜的存活和代谢稳态至关重要。我们以及其他人已经揭示了一个新的特点，透镜连接蛋白参与促进上皮纤维分化和透镜的发展。我们的长期目标是了解连接蛋白分子在透镜发育和稳态中的分子机制和功能意义。本申请的目的是了解Cx 50在细胞分化和透镜生长和发育中的机制作用。核心假设是：（1）Cx 50通过与细胞周期调节因子相互作用而在功能上参与透镜分化，其作用独立于间隙连接;（2）MIP促进Cx 50在透镜纤维中的定位和稳定。我们将追求两个具体目标：1）。明确Cx 50的PEST结构域在上皮纤维分化和透镜发育中的分子机制。2）。确定MIP与Cx 50相互作用的功能意义。本研究的创新点之一是旨在剖析透镜连接蛋白非传统功能的分子机制。此外，该研究计划将使用我们建立的禽逆转录病毒方法作为主要工具，用于实验操作的主要鸡透镜培养物以及体内鸡透镜。更重要的是，从鸡透镜中获得的发现将通过使用野生型和基因敲除小鼠模型的拟议研究进行验证和补充。我们期望我们的实验结果将为理解Cx 50在分化透镜纤维中的功能意义和调控机制提供分子基础，并有望对定义透镜连接蛋白参与透镜生长和发育的过程产生重大积极影响。我们的研究成果将是重要的，因为新的知识发现将有助于更广泛地了解上皮纤维分化和透镜发育的机制方面。公共卫生相关性：白内障是最常见的眼科疾病之一，也是全球失明的主要原因之一。拟议的研究活动将有助于了解透镜功能和形成的生物过程，从长远来看，应能为白内障治疗策略以及药物发现和开发的新思路和潜在目标作出新的贡献。

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.