Hypoxia Regulation of the Lens

项目概要/摘要 本申请旨在确定实现结构所需的新机制和调控途径 和眼睛透镜的功能。该透镜由上皮细胞的表面层组成， 并且在整个生命过程中，分化成构成透镜的核心和主体的透镜纤维细胞。实现 新形成的透镜纤维细胞必须完成一个有序的 细胞重塑程序的特点是细胞器的完全消除和紧密的 特异性透镜蛋白的受控表达。透镜纤维细胞重塑程序的中断导致 缺陷的透镜结构和白内障形成，因此，这些机制和调节的鉴定 通路对于促进我们对成熟透镜形成和病理学的理解至关重要。我们最近 发现红细胞中线粒体降解的关键调节因子BNIP 3L是红细胞生长所必需的。 胚胎透镜中线粒体、内质网和高尔基体的特异性消除 形成无细胞器的透镜区。这些研究确定了消除非- 在胚胎透镜纤维细胞重塑过程中， BNIP 3L在内质网和高尔基体降解中的功能。拟议的实验 在AIM 1中，现在试图通过建立BNIP 3L在消除中的新要求来推进这些发现， 这些细胞器在成人透镜纤维细胞重塑过程中的作用，并试图揭示其机制， 调节途径和BNIP 3L依赖性消除所需的辅助蛋白。缺乏血液 供应所述透镜包含从所述透镜表面到所述透镜芯逐渐减小的氧梯度。实验目的 2旨在检验新假设，即透镜缺氧是透镜结构的新要求， 通过缺氧依赖性控制透镜纤维细胞中的细胞器消除和 调控关键基因，包括BNIP 3L、细胞周期退出蛋白p27和结构蛋白CP 49， 通过激活低氧反应的主要调节因子，低氧诱导转录因子 HIF 1a。这些目标的成功完成将对我们的理解产生重大的长期影响 是导致眼透镜结构成熟和透明功能的细胞重塑途径。的 这些结果也有望促进对细胞重塑途径的鉴定， 更复杂组织的形成和功能。

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.