Regulatory mechanisms of the protective function of alphaA- & alphaB-crystallins in retinal neurons and glia

αA保护功能的调节机制

• 批准号: 326938900
• 负责人: Dr. Anne Rübsam
• 金额: --
• 依托单位: Klinik für Augenheilkunde (CVK)
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/326938900?language=en
• 关键词: Regulatory; mechanisms; protective; function; alphaA

Still today Diabetic retinopathy (DR) accounts for the most common reason blindness in industrial nations with a further increasing rate. Since the last decade there is a rethinking regarding the pathophysiology of the disease; away from the vasculature changes of the late stages of DR towards the early changes in the neurons and their supporting glial cells. Hence there is a new perspective regarding the therapeutic approaches in the treatment of DR. Recently Fort et al. in Ann Arbor, Michigan revealed that a family of proteins, the alpha--crystallins are highly upregulated in animal models of type 1 and 2 diabetes. Immunoreactivity for alpha-crystallin increases in the retinas of patients with diabetes, confirming that the changes observed in animal models are relevant to the human pathology alpha-Crystallins protect retinal cells (neurons and Müller glial cells) from acute stress-induced cell death; however, in chronic diabetes the protective properties of crystallins are altered and retinal cell death still occurs. Analysis of retinal lysates from diabetic animals shows post-translational modifications of the crystallin proteins, although the exact nature and functional consequences of these post-translational modifications are currently unknown. A better understanding of the biochemical changes to crystallin proteins caused by chronic diabetes, the exact function of cyrstallin proteins in the retina during diabetes and how these changes affect the protective functions of crystallin proteins would expand our knowledge of the innate neuroprotective mechanisms in the retina and provide a necessary first step toward manipulating or optimizing the function of neuroprotective proteins in retinal diseases. The long-term goal of this research is to determine how the protective functions of alpha-crystallins can be manipulated to preserve vision in patients with diabetes. The objective of this project is to identify mechanisms by which diabetes modulates the function of alphaA- and alphaB-crystallin proteins in retinal cells and how these mechanisms are modified during diabetes.

时至今日，糖尿病视网膜病变 (DR) 仍然是工业国家失明的最常见原因，而且发病率还在进一步上升。自过去十年以来，人们开始重新思考该疾病的病理生理学。从 DR 晚期的脉管系统变化转向神经元及其支持神经胶质细胞的早期变化。因此，对于 DR 的治疗方法有了新的视角。最近福特等人。密歇根州安娜堡市的研究人员发现，α-晶状体蛋白这一蛋白质家族在 1 型和 2 型糖尿病动物模型中高度上调。糖尿病患者视网膜中α-晶状体蛋白的免疫反应性增加，证实在动物模型中观察到的变化与人类病理学相关。α-晶状体蛋白可保护视网膜细胞（神经元和米勒神经胶质细胞）免受急性应激诱导的细胞死亡；然而，在慢性糖尿病中，晶状体蛋白的保护特性发生改变，视网膜细胞死亡仍然发生。对糖尿病动物视网膜裂解物的分析显示了晶状体蛋白的翻译后修饰，尽管这些翻译后修饰的确切性质和功能后果目前尚不清楚。更好地了解慢性糖尿病引起的晶状体蛋白的生化变化、糖尿病期间晶状体蛋白在视网膜中的确切功能以及这些变化如何影响晶状体蛋白的保护功能，将扩大我们对视网膜先天神经保护机制的了解，并为操纵或优化视网膜疾病中神经保护蛋白的功能提供必要的第一步。这项研究的长期目标是确定如何操纵α-晶状体蛋白的保护功能来保护糖尿病患者的视力。该项目的目的是确定糖尿病调节视网膜细胞中 αA- 和 αB- 晶状体蛋白功能的机制，以及这些机制在糖尿病期间如何改变。