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Towards Improved Early Diagnosis of Neurodegenerative Diseases - Noninvasive Investigations of Retinal Metabolism Using Fluorescence Lifetime and Anisotropy Analysis of the Cellular Redox State

改善神经退行性疾病的早期诊断 - 利用荧光寿命和细胞氧化还原状态的各向异性分析对视网膜代谢进行无创研究

基本信息

批准号：
234540519
负责人：
Dr. Martin Hammer
金额：
--
依托单位：
Institut für Biomedizinische Technik und Informatik
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2015-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/234540519?language=en
关键词：
Towards Improved Early Diagnosis Neurodegenerative

项目摘要

Neurodegenerative diseases (ND) constitute a dramatic medical and socio-economic challenge for the increasingly ageing population. Despite their diverse aetiology, neuronal pathophysiology leading to cell dysfunction and death seems to have common downstream pathways. As the mitochondrion provides most of cellular ATP and regulates apoptosis, it creates a central link between cell death and the primary cause of neurodegeneration. Moreover, mitochondrial dysfunction (MD) has been increasingly implicated as a crucial step in the pathogenesis of not only major ND (e.g., Alzheimer's disease, etc.), but also ophthalmological disorders such as diabetic retinopathy (DR), age-related macular degeneration (AMD) and glaucoma. Early diagnosis of MD might help to establish and improve therapeutic approaches, but more importantly extend the current understanding of the initial processes of neurodegeneration. Therefore, detecting initial pre-apoptotic changes in the energy metabolism of mitochondria would be of utmost interest.As an emerging technique in ophthalmological diagnostics, ocular fundus autofluorescence (FAF) imaging can be a powerful technique to reveal important details on pathological alterations. We developed a new noninvasive optical imaging technique called fluorescence lifetime imaging ophthalmoscopy (FLIO), which is based on spectral-resolved fluorescence lifetime. As opposed to steady state fluorescence, FLIO allows accurate measurement of changes in the microenvironment of endogenous fluorophores. Thereby, it enables probing of redox equilibria of the coenzymes NAD(P)H and flavins as well as the detection of partially toxic metabolic by-products. First clinical studies using FLIO revealed a significant discrimination of diabetic patients, AMD-patients and controls. However, the interpretation of in vivo measurements requires deeper insights into the pathological alterations of FAF.Therefore, the main goal of this project is to establish a detailed connection between pathological changes of retinal autofluorescence and initial pre-apoptotic MDs. To investigate the pathogenesis of retinal degeneration (i.e. DR and AMD) noninvasive optical techniques and a variety of biochemical cell assays will be employed. Particularly, spectral- and time-resolved fluorescence as well as fluorescence anisotropy will be used to probe the concentrations of free and protein-bound NADH and flavins in cell and organ culture models in response to hypoxy, hyperglycemia and photooxidative stress. For that purpose, a new recording technique as well as new models and algorithms for the analysis of fluorescence data will be developed. Altogether, this may provide great advances in early diagnosis of DR and AMD, and thus will support new therapeutic strategies for retinal degeneration affecting millions of patients. Moreover, our investigations will considerably contribute to a fundamental understanding of essential mechanisms involved in the development of ND.

神经退行性疾病（ND）对日益老龄化的人口构成了巨大的医疗和社会经济挑战。尽管它们的病因不同，但导致细胞功能障碍和死亡的神经元病理生理学似乎有共同的下游途径。由于线粒体提供大部分细胞ATP并调节细胞凋亡，它在细胞死亡和神经变性的主要原因之间建立了中心联系。此外，线粒体功能障碍（MD）越来越多地被认为是不仅是主要ND（例如，阿尔茨海默病等），还包括眼科疾病，例如糖尿病性视网膜病（DR）、年龄相关性黄斑变性（AMD）和青光眼。MD的早期诊断可能有助于建立和改善治疗方法，但更重要的是扩展了目前对神经退行性变初始过程的理解。因此，检测线粒体能量代谢的初始凋亡前变化将是最大的interests.Our新兴技术在眼科诊断，眼底自发荧光（FAF）成像可以是一个强大的技术，以揭示重要的细节病理改变。我们开发了一种新的无创光学成像技术称为荧光寿命成像检眼镜（FLIO），这是基于光谱分辨荧光寿命。与稳态荧光相反，FLIO允许精确测量内源性荧光团微环境的变化。因此，它能够探测辅酶NAD（P）H和黄素的氧化还原平衡，以及检测部分有毒的代谢副产物。使用FLIO的第一个临床研究揭示了糖尿病患者、AMD患者和对照的显著区别。然而，在体内测量的解释需要更深入地了解FAF的病理变化。因此，本项目的主要目标是建立视网膜自发荧光的病理变化和初始凋亡前MDs之间的详细联系。为了研究视网膜变性（即DR和AMD）的发病机制，将采用非侵入性光学技术和各种生化细胞测定。特别是，光谱和时间分辨荧光以及荧光各向异性将用于探测细胞和器官培养模型中的游离和蛋白质结合的NADH和黄素的浓度，以响应低氧，高血糖和光氧化应激。为此，将开发一种新的记录技术以及用于分析荧光数据的新模型和算法。总之，这可能在DR和AMD的早期诊断方面提供巨大的进步，从而将支持影响数百万患者的视网膜变性的新治疗策略。此外，我们的调查将大大有助于从根本上了解参与ND发展的重要机制。