Developin in-vitro models of A beta toxicity: Complementary yeast and human stem cell approaches

 描述(由申请者提供)：开发A？毒性的体外模型：互补酵母和人类干细胞方法超过500万美国人已被诊断为阿尔茨海默病(AD)。随着老年患者数量的增加，预计未来几年患者数量将会增加。反过来，不断增长的患者群体又需要增加资金来治疗和护理受影响的个人。目前，没有可用的治疗方法可以使AD患者增加五年或更长时间的无症状生命。开发新的治疗化合物的一个主要障碍是无法获得受AD影响的神经组织类型用于研究。为了解决这个问题，许多研究小组开发了体外模型系统，以促进对疾病过程的研究。我们的团队之前已经建立了酿酒酵母淀粉样β42(A？42)毒性的模型。A42通常被认为是AD进展过程中神经细胞凋亡的罪魁祸首。这种酵母模型已被用于遗传筛选和发现调节A？42毒性的治疗靶点。当前提案的目标1是通过功能丧失研究进一步确定这些遗传修饰因子的特征。虽然酵母的易操纵性为识别新的治疗靶点提供了一个强大的模型，但在考虑进行治疗测试之前，这些靶点必须在临床相关的模型中得到确认。最近，人类胚胎干细胞(HES)来源的神经元已被证明在体外环境下概括了神经退行性疾病的重要方面。因此，在目标2中，我建议建立一个A？42毒性的补充性人类干细胞模型。此外，在AIM 3中，我将使用已建立的人类干细胞模型来证实我们之前在酵母中发现的临床相关细胞类型，并探讨ApoE基因对A？42毒性的影响。总而言之，这些研究将更深入地挖掘A？42毒性的可能治疗靶点，这可能导致在未来的小分子筛选中发现有效的化合物。

 DESCRIPTION (provided by applicant): Developing In-Vitro Models of Aß Toxicity: Complementary Yeast and Human Stem Cell approaches over 5 million americans have been diagnosed with Alzheimer's disease (AD). This patient population is expected to increase in the coming years as the number of elderly individuals grows. In turn, this growing patient population confers a need for increased funding to treat and care for affected individuals. Currently, no available treatments can add five or more years of symptom-free life to an individual with AD. One major obstacle to the development of novel therapeutic compounds has been the inability to obtain the neural tissue types impacted by AD for study. To address this issue, many research groups have developed model in vitro systems which facilitate the study of the disease course. Our group has previously developed a Saccharomyces cerevisiae model of amyloid beta 42 (Aß42) toxicity. Aß42 is commonly thought to be the culprit which underlies the neuronal apoptosis which occurs during AD progression. This yeast model has been used in genetic screens and uncovered therapeutic targets which modulate Aß42 toxicity. AIM 1 of the current proposal is to further characterize these genetic modifiers through loss-of-function studies. While the tractability of yeast provides a powerful model for identifying novel therapeutic targets these targets must be confirmed in clinically relevant models before therapeutic testing can be contemplated. Recently, human embryonic stem (hES) cell derived neurons have proven to recapitulate important aspects of neurodegenerative disorders in an in vitro setting. Therefore, in AIM 2 I propose to establish a complimentary human stem cell model of Aß42 toxicity. Furthermore, in AIM 3 I will use the established human stem cell model to confirm our previous findings in yeast in clinically relevant cell types and probe the influence of ApoE genotype on Aß42 toxicity. Together, these studies will delve deeper into possible therapeutic targets for Aß42 toxicity which could lead to efficacious compounds in future small molecule screens.