Hypoxia Regulation of the Lens

项目摘要/摘要 这项申请寻求确定实现该结构所需的新机制和调控途径 和眼睛晶状体的功能。晶状体由表层的上皮细胞组成，在胚胎发育过程中， 在整个生命过程中，分化成晶状体纤维细胞，构成晶状体的核心和主体。要实现 其成熟的结构和透明的功能，新形成的晶状体纤维细胞必须完成一系列 以彻底消除细胞器和紧密结合为标志的细胞重塑方案 特殊晶状体蛋白的受控表达。晶状体纤维细胞重塑程序的中断导致 晶状体结构缺陷与白内障的形成使这些机制的识别和调控 通路对于促进我们对成熟晶状体形成和病理的理解是至关重要的。我们最近做了 发现红细胞中线粒体降解的关键调节因子，称为BNIP3L，是 胚胎晶状体中线粒体、内质网和高尔基体的特异性消除 晶状体无细胞器区的形成。这些研究确定了消除非 胚胎晶状体纤维细胞重塑中的核细胞器及其建立的一种全新的 BNIP3L在内质网和高尔基体降解中的作用建议进行的实验 在AIM1中，现在试图通过建立在消除中对BNIP3L的新要求来推进这些发现 这些细胞器在成人晶状体纤维细胞重塑过程中的作用，并试图揭示其机制， 它们依赖于BNIP3L的消除所需的调控途径和辅助蛋白。缺少鲜血 供应镜片包含从镜片表面到镜片核心的逐渐减小的氧气梯度。实验目的 2旨在检验晶状体低氧是晶状体结构的新要求这一新假说，以及 低氧依赖控制晶状体纤维细胞细胞器消除的透明度和 关键基因的调控，包括BNIP3L、细胞周期退出蛋白p27和结构蛋白CP49， 通过激活低氧反应的主要调节因子，低氧诱导的转录因子 HIF1a。这些目标的成功实现将对我们的理解产生重大的长期影响 导致眼晶状体结构成熟和透明功能的细胞重塑途径。这个 这一结果也有望促进对细胞重塑途径的识别 更复杂的组织的形成和功能。

Project Summary/Abstract This application seeks to identify novel mechanisms and regulatory pathways required to achieve the structure and function of the eye lens. The lens consists of a surface layer of epithelial cells that during embryogenesis, and throughout life, differentiate into lens fiber cells that make up the core and bulk of the lens. To achieve their mature structure and transparent function, newly-formed lens fiber cells must complete a sequential program of cellular remodeling hallmarked by the complete elimination of cellular organelles and the tightly controlled expression of specialized lens proteins. Disruption of the lens fiber cell remodeling program causes defective lens structure and cataract formation so that identification of these mechanisms and regulatory pathways is critical for advancing our understanding of mature lens formation and pathology. We have recently discovered that a key regulator of mitochondrial degradation in erythrocytes, called BNIP3L, is required for the specific elimination of mitochondria, endoplasmic reticulum and Golgi apparatus in the embryonic lens during formation of the lens organelle-free zone. These studies identify the first requirement for the elimination of non- nuclear organelles during the remodeling of embryonic lens fiber cells and they establish an entirely novel function for BNIP3L in the degradation of endoplasmic reticulum and Golgi apparatus. Experiments proposed in AIM1 now seek to advance these findings by establishing a novel requirement for BNIP3L in the elimination of these organelles during the remodeling of adult lens fiber cells and they seek to reveal the mechanisms, regulatory pathways and auxiliary proteins required for their BNIP3L-dependent elimination. Lacking a blood supply the lens contains a diminishing oxygen gradient from the lens surface to the lens core. Experiments AIM 2 are designed to test the novel hypothesis that lens hypoxia is a novel requirement for lens structure and transparency through the hypoxia-dependent control of organelle-elimination in lens fiber cells and the regulation of critical genes including BNIP3L, the cell-cycle exit protein p27 and the structural protein CP49, through activation of the master regulator of the hypoxic response, hypoxia-inducible transcription factor HIF1a. The successful completion of these AIMs will have a significant long-term impact on our understanding of the cellular remodeling pathways leading the mature structure and transparent function of the eye lens. The results are also expected to advance the identification of cellular remodeling pathways required for the formation and function of more complex tissues.