Hypoxia Regulation of the Lens

晶状体的缺氧调节

• 批准号: 10456991
• 负责人: Marc Kantorow
• 金额: $ 35.9万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456991
• 关键词: Adult; Birth; Cataract; Cataract Extraction; Cell Cycle; Cells; Cellular Structures; Chick; Complex; Crystalline Lens; Crystallins; Data; Development; Embryo; Embryonic Development; Endoplasmic Reticulum; Environment; Epithelial Cells; Erythrocytes; Event; Exhibits; Genes; Genetic Transcription; Golgi Apparatus; HRK gene; Health; Hyperoxia; Hypoxia; Knockout Mice; Lead; Lens Fiber; Life; Link; Mitochondria; Mus; Organelles; Oxygen; Parkin; Pathology; Pathway interactions; Population; Prevention therapy; Proteins; Regulation; Regulatory Pathway; Reporting; Structural Protein; Structure; Surface; Testing; Tissues; Transcriptional Regulation; Vascular blood supply; Visual; cell growth regulation; cyclin-dependent kinase inhibitor 1B; design; disability; experimental study; fiber cell; insight; lens; mouse model; novel; novel therapeutics; overexpression; programs; protein expression; response; success; transcription factor

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.

项目概要/摘要 该申请旨在确定实现该结构所需的新机制和监管途径 和眼睛晶状体的功能。晶状体由上皮细胞表面层组成，在胚胎发生过程中， 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。达到 由于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顺序 细胞重塑程序的特点是完全消除细胞器和紧密结合 特殊晶状体蛋白的受控表达。晶状体纤维细胞重塑程序中断的原因 有缺陷的晶状体结构和白内障形成，以便识别这些机制和调节 通路对于增进我们对成熟晶状体形成和病理学的理解至关重要。我们最近有 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 他们在胚胎晶状体纤维细胞重塑过程中发现了核细胞器，并建立了一种全新的 BNIP3L 在内质网和高尔基体降解中的功能。提议的实验 AIM1 现在寻求通过在消除中建立 BNIP3L 的新要求来推进这些发现 在成年晶状体纤维细胞的重塑过程中，这些细胞器的变化，他们试图揭示其机制， BNIP3L 依赖性消除所需的调节途径和辅助蛋白。缺少一滴血 供应镜片从镜片表面到镜片核心的氧气梯度递减。实验目的 2旨在测试晶状体缺氧是晶状体结构的新要求的新假设 通过缺氧依赖性控制晶状体纤维细胞中的细胞器消除和 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， 通过激活缺氧反应的主调节因子缺氧诱导转录因子 HIF1a。这些 AIM 的成功完成将对我们的理解产生重大的长期影响 细胞重塑途径导致晶状体的成熟结构和透明功能。这 预计结果还将促进对细胞重塑所需途径的识别。 更复杂组织的形成和功能。