Pathophysiologie und Topographie von Schadensmechanismen in AMD-relevanten Tiermodellen (Pathophysiology and topographical distribution of disease mechanisms in animal models relevant for AMD)

大多数视网膜变性的研究已经被转基因动物的可用性所推动，转基因动物允许对与这些疾病病程相关的功能、生化和组织学变化进行详细、高效的分析。然而，目前还没有令人满意的AMD模型。因此，本项目的目的是找到AMD的病理生理模型或至少其某些方面。为了实现这一目标，我们将研究一种新的转基因小鼠- TIMP3敲入蛋白-这是Sorsby眼底营养不良（SFD）的模型。由于SFD具有Bruch膜改变和脉络膜新生血管的特征，TIMP-3小鼠是AMD模型的有希望的候选者。小鼠将在体内进行电生理和眼底成像研究，并辅以组织学和免疫组织化学工作。在报道了维生素a对SFD患者的强大有益作用之后，我们将进一步尝试通过限制/补充维生素a来加强/改善转基因小鼠的表型。在获得TIMP3基因敲除后，该模型也将纳入本项目。在后期拨款期间，将对Weber教授小组检测rpe特异性基因后产生的动物模型进行测试，并对已确定的AMD模型进行治疗性研究。此外，麻省理工大学的Thanos教授还为电生理研究提供了一种有趣的大鼠ARMD模型。我们的项目在Schwerpunkt中发挥着核心作用，因为它结合了动物模型中详细的眼科和功能测试的努力，这些测试也提供给其他参与小组。

Research in most retinal degenerations has been boosted by the availability of transgenic animals that permit the detailed, time-efficient analysis of functional, biochemical, and histological changes associated with the course of these diseases. However, there is no satisfactory model for AMD yet. The purpose of this project is thus to find a pathophysiological model for AMD or at least some of its aspects. To achieve that goal, we will study a new transgenic mouse - the TIMP3 knockin - which is a model for Sorsby's Fundus dystrophy (SFD). As SFD features changes to Bruch's membrane and a choroidal neovascularization, TIMP-3 mice are promising candidates for an AMD model. The mice will be studied in vivo with electrophysiological and fundus imaging methods, accompanied by histological and immunohistochemical work. Following reports of a strong beneficial effect of Vitamin A in SFD patients, we will further attempt to intensify/ameliorate the phenotype in the transgenic mice by means of Vitamin A restriction/supplementation. After the availability of a TIMP3 knockout, this model will also be included in this project. In the later grant periods, animal models that will be generated following the detection of RPE-specific genes by Professor Weber's group will be tested, and therapeutical studies in identified AMD models conducted. Additionally an interesting rat model on ARMD was offered for electrophysiological investigations by Professor Thanos from Münster. Our project has a central role within the Schwerpunkt as it combines the efforts regarding detailed ophthalmological and functional tests in animal models which are also offered to other which are also offered to other participating groups.