Mitochondrial and metabolic dysfunctions in the progeroid Cockayne syndromeand therapeutic perspectives

早衰科凯恩综合征的线粒体和代谢功能障碍及治疗前景

• 批准号: 445959678
• 负责人: Professor Dr. Mark-Jürgen Berneburg
• 金额: --
• 依托单位: Klinik und Poliklinik für Dermatologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/445959678?language=en
• 关键词: Mitochondrial; metabolic; dysfunctions; progeroid; Cockayne

Cockayne syndrome (CS) is a rare genetic disease displaying dramatically precocious ageing, severe neurological defects, UV-hypersensitivity, and a short life expectancy with no treatment to date. This project is based on the recent identification and validation of a defective pathway in cells of CS patients that is uncoupled from the well-documented DNA repair defect, and rather involves mitochondrial and metabolic impairment. The extent and the consequences of this metabolic impairment at the molecular and cellular level remain to be elucidated and are the main subject of the present proposal. Importantly, CS displays a wide spectrum of severity that constitutes a clinical continuum the reasons of which are not understood. Our working hypothesis is that metabolic alterations are largely responsible for the different clinical outcomes in CS. Beyond unbalanced energetics, metabolic changes affect regulatory pathways, protection from ROS, and the epigenetic landscape.Our objective is to dissect the metabolic impairment in CS and its consequences on cellfunction, and pave the way to a therapeutic intervention that includes protective effects of metabolism against the aging process. Indeed, the full rescue of CS cellular alterations by a porphyrin derivative acting on oxidative and nitrosative stress, MnTBAP, that we previously demonstrated, is the key element for a novel therapy. MnTBAP obtained an Orphan Drug Designation for CS and is well tolerated in vivo. The present application has three primary aims. Aim1: Link the severity of CS clinical symptoms, and thereby the susceptibility to respond to MnTBAP treatment, to altered mitochondrial parameters. For this, we will assess mitochondrial impairment and its rescue by treatment. Aim 2. Link CS defects with metabolic changes in patient cells using a systematic approach to major metabolic pathways and their protective effect against ROS. Results in patient cells will be integrated with the disease specific scoring system developed by consortium members. Aim 3. Assess the extent of mitochondrial and metabolic alterations on CS-derived iPS cells, neuroectodermal organoids (that only our consortium has produced from CS-iPS cells). On these cells/structures will be applied the abovementioned approaches, and we will consolidate preclinical data on the effect MnTBAP. This project relies on a combination of novel concepts, a unique collection of patient-derived biomaterial, and direct link between research scientists and clinicians to dissect the underlying causes and open to a therapeutic intervention for CS.

Cockayne综合征（CS）是一种罕见的遗传性疾病，表现出显着的早熟衰老，严重的神经系统缺陷，紫外线过敏，和预期寿命短，没有治疗的日期。该项目基于最近对CS患者细胞中缺陷途径的鉴定和验证，该缺陷途径与有据可查的DNA修复缺陷脱钩，而是涉及线粒体和代谢损伤。这种代谢障碍在分子和细胞水平上的程度和后果仍有待阐明，这是本提案的主要主题。重要的是，CS表现出广泛的严重程度，构成了临床连续性，其原因尚不清楚。我们的工作假设是，代谢改变在很大程度上负责CS的不同临床结果。除了不平衡的能量，代谢变化影响调节途径，保护ROS，和表观遗传landscape.Our的目标是解剖CS的代谢损伤及其对细胞功能的后果，并铺平了道路的治疗干预，包括对衰老过程中的代谢保护作用。事实上，我们先前证明的通过卟啉衍生物作用于氧化和亚硝化应激MnTBAP来完全拯救CS细胞改变是新疗法的关键要素。MnTBAP获得了CS的孤儿药认定，并且在体内耐受性良好。本申请具有三个主要目的。目的1：将CS临床症状的严重程度以及对MnTBAP治疗的敏感性与线粒体参数的改变联系起来。为此，我们将评估线粒体损伤及其治疗挽救。目标二。使用系统方法将CS缺陷与患者细胞中的代谢变化联系起来，以了解主要代谢途径及其对ROS的保护作用。患者细胞的结果将与联盟成员开发的疾病特异性评分系统相结合。目标3。评估CS衍生的iPS细胞、神经外胚层类器官（只有我们的联合体从CS-iPS细胞产生）的线粒体和代谢改变的程度。在这些细胞/结构上将应用上述方法，并且我们将巩固关于MnTBAP效果的临床前数据。该项目依赖于新概念的组合，患者来源的生物材料的独特集合，以及研究科学家和临床医生之间的直接联系，以剖析根本原因并开放CS的治疗干预。