The regulation of lens fiber cell differentiation

描述（由申请人提供）：白内障的基本病理通常可以证明与晶状体纤维细胞从其增殖过渡区前体分化的缺陷有关。此外，白内障手术的副作用，如后囊膜混浊和索默林氏环的形成，会降低患者的长期视力，特别是那些安装了最新一代可调节人工晶状体的患者。这些研究旨在阐明正常晶状体纤维细胞分化的转录机制，以及晶状体细胞对损伤的转录反应，特别是白内障摘除后的损伤。具体目的之一是确定允许Prox1同时作为转录激活因子和抑制因子的分子机制。由于Prox1对晶状体纤维细胞分化至关重要，这将使我们能够确定Prox1如何调节其多种功能。具体目的二旨在研究Zeb家族的转录因子如何参与晶状体发育，并验证这些因子也参与晶状体损伤反应的假设。这些研究将确定晶状体损伤后控制晶状体发育的分子机制是如何被重复利用的。特异性目标3旨在确定HMGN蛋白在晶状体中的功能。由于已知这些蛋白质参与染色质重塑导致基因激活，这些研究将使我们了解晶体蛋白的巨大转录活性是如何完成的。这些补充性的研究应该提供洞察晶状体纤维细胞分化是如何被控制的，以及晶状体损伤后这一过程是如何被吸收的。公共卫生相关性：白内障是世界上最常见的失明形式。在美国，白内障摘除是老年人最常见的门诊手术，2005年花费超过3.43亿美元（http://www.cms.hhs.gov/MedicareMedicaidStatSupp/）。然而，接受白内障治疗的10- 20%的老年人和近100%的儿童患者会出现后囊膜混浊（PCO），这需要额外的治疗，并可能导致视力下降。此外，人工晶状体（iol）植入物的开发正在付出很多努力，以恢复白内障手术后眼睛适应（建立近焦）的能力。长期调节恢复的一个主要障碍是被人工晶状体困在晶状体赤道的晶状体上皮细胞通常会使晶状体皮层再生，从而降低睫状肌适应植入的人工晶状体的能力。本研究旨在解决与后发性白内障发育和晶状体纤维细胞分化的分子机制有关的未解决的问题，以防止白内障手术的副作用。

DESCRIPTION (provided by applicant): The underlying pathology of cataract can often be demonstrated to involve defects in the differentiation of lens fiber cells from their proliferative transitional zone precursors. Further, the side effects of cataract surgery such as posterior capsular opacification and Soemmering's ring formation can reduce the long term visual outcome for patients, particularly those fitted with the newest generation of accommodating intraocular lenses. These studies seek to elucidate the transcriptional mechanisms responsible for normal lens fiber cell differentiation and the transcriptional response of lens cells to injury, especially following cataract extraction. Specific aim one seeks to determine the molecular mechanisms that allow Prox1 to function as both a transcriptional activator and repressor. Since Prox1 is essential for lens fiber cell differentiation, this will allow us to determine how Prox1 regulates its diverse functions. Specific aim two seeks to investigate how transcription factors of the Zeb family participate in lens development and tests the hypothesis that these factors also participate in the lens injury response. These investigations will determine how the molecular mechanisms controlling lens development are reused following lens injury. Specific aim three seeks to determine the function of HMGN proteins in the lens. Since these proteins are known to be involved in chromatin remodeling resulting in gene activation, these studies will allow us to understand how the enormous transcriptional activity of crystallins is accomplished. These complementary studies should provide insight into how lens fiber cell differentiation is controlled and how this process is co-opted following lens injury. PUBLIC HEALTH RELEVANCE: Cataracts are the most prevalent form of blindness worldwide. In the USA, cataract removal is the most common outpatient surgical operation performed on the elderly costing over 343 million dollars in 2005 (http://www.cms.hhs.gov/MedicareMedicaidStatSupp/). However, 10- 20% of elderly and nearly 100% of pediatric patients treated for cataract develop posterior capsular opacification (PCO) which requires additional treatments and can result in reduced visual outcomes. Further, much effort is being exerted towards the development of intraocular lens (IOLs) implants that restore the ability of the eye to accommodate (establish near focus) after cataract surgery. A major impediment to long term restoration of accommodation is that lens epithelial cells trapped at the lens equator by the IOL often regenerate the lens cortex which reduces the ability of the ciliary muscles to accommodate the implanted IOL. This proposal addresses unanswered questions related to the molecular mechanisms of PCO development and lens fiber cell differentiation with the long term goal of preventing the side effects of cataract surgery.