Enhancing photoreceptor integration using microglia-derived secreted factors

 描述(申请人提供)：视网膜，像神经系统的许多其他区域一样，受到各种遗传性和获得性退行性疾病的影响。这些情况通常会导致视网膜中主要的感光细胞--光感受器的退化。尽管失去了光感受器，但视网膜内部电路多年来一直完好无损，这使得光感受器替代作为一种潜在的治疗方法成为可能。细胞替换策略很重要，因为哺乳动物视网膜中光感受器的丧失与驻留细胞的任何有效再生无关。细胞替代的一个潜在来源可能是多能干细胞。有许多小组正在研究干细胞来源的RPE的潜力，包括一项批准的RPE细胞替代治疗AMD和Stargardt营养不良的临床试验。然而，随着疾病的发展到视力丧失，患者也需要更换丢失的光感受器细胞。尽管一些研究小组已经证明了小鼠视网膜中光感受器的整合，但总体效率确实很低。 此外，小胶质细胞在这一过程中的作用在很大程度上还没有被探索。这项提案旨在研究小胶质细胞衍生的神经营养因子在视网膜修复和再生医学中的作用。我们将使用跨物种的方法来识别和进行苍蝇的基础研究，并将结果应用于哺乳动物的视网膜。

 DESCRIPTION (provided by applicant): The retina, like many other regions of the nervous system, is subject to a variety of inherited and acquired degenerative conditions. These conditions often result in the degeneration of the photoreceptors, the main light sensing cells in the retina. Despite the loss of photoreceptors, the inner retinal circuitry is intact for many year, and this has led to the possibility of photoreceptor replacement as a potential therapy. Cell replacement strategy is important as the loss of photoreceptors in the mammalian retina is not associated with any effective regeneration from resident cells. A potential source of cellular replacement could be pluripotent stem cells. There are a number of groups looking into the potential of stem cell derived RPE including an approved clinical trial for RPE cell replacement for AMD and Stargardt dystrophy. However, as the disease progresses to vision loss, patients will require replacement of the lost photoreceptor cells as well. Although a number of groups have shown integration of photoreceptors in the mouse retina, the overall efficiency is really low. Additionally, the role of the microglia in this process has largely been unexplored. This proposal aims to look at the role of microglia-derived neurotrophic factors in both retinal repair and regenerative medicine. We will use a cross-species approach to identify and carry out basic studies in flies and apply the result in mammalian retinas.