The regulation of lens fiber cell differentiation

描述（由申请人提供）：白内障的潜在病理学通常可以证明涉及透镜纤维细胞从其增殖性移行区前体分化的缺陷。此外，白内障手术的副作用，如后囊膜混浊和Soemmering环形成，可能会降低患者的长期视力结果，特别是那些安装了最新一代可调节人工晶状体的患者。这些研究试图阐明负责正常透镜纤维细胞分化的转录机制和透镜细胞对损伤的转录反应，特别是在白内障摘除术后。具体目标是确定允许Prox 1作为转录激活因子和抑制因子发挥作用的分子机制。由于Prox 1是必不可少的透镜纤维细胞分化，这将使我们能够确定Prox 1如何调节其不同的功能。具体目标二旨在研究Zeb家族的转录因子如何参与透镜发育，并检验这些因子也参与透镜损伤反应的假设。这些研究将确定控制透镜发育的分子机制在透镜损伤后如何被重新利用。第三个具体目标是确定HMGN蛋白在透镜中的功能。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。这些补充研究应该提供深入了解如何控制透镜纤维细胞分化，以及如何在透镜损伤后选择这一过程。公共卫生相关性：白内障是全球最常见的失明形式。在美国，白内障摘除是对老年人进行的最常见的门诊外科手术，2005年花费超过3.43亿美元（http：//www.cms.hhs.gov/MedicareMedicaidStatSupp/）。然而，10- 20%的老年人和近100%的儿童患者接受白内障治疗后会出现后囊膜混浊（PCO），这需要额外的治疗，并可能导致视力下降。此外，人们正在努力开发眼内透镜（IOL）植入物，该植入物在白内障手术后恢复眼睛的调节能力（建立近焦点）。调节长期恢复的主要障碍是被IOL捕获在透镜赤道处的透镜上皮细胞经常再生透镜皮质，这降低了睫状肌调节植入IOL的能力。该提案解决了与PCO发展和透镜纤维细胞分化的分子机制相关的未回答的问题，其长期目标是预防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.