Mechanisms of progressive neurodegeneration: combining forward genetic screens in

描述（由申请人提供）：年龄是神经退行性疾病的主要风险因素。随着社会年龄的神经退行性变变得越来越普遍，但这种复杂情况下的分子和细胞机制仍然在很大程度上未知。该提案的目标是探索新的途径，以公正的方式调查神经退行性变的机制。利用果蝇遗传学的力量进行的错误表达筛选被用来识别可能与迟发性行为缺陷（衰老）有关的基因。因此，新的基因被确定为参与晚期神经元功能障碍，然后可以在果蝇中枢神经系统的特征和验证相结合的遗传学，成像和行为。基因功能改变的影响也可以在小鼠大脑中通过逆转录病毒介导的年轻成年人和衰老大脑神经元中的表达进行测试和验证。这些研究中出现的细胞自主效应将在很大程度上有助于理解候选基因影响的神经元功能的具体方面。与此同时，将根据果蝇中鉴定的基因建立转基因小鼠模型。小鼠大脑中改变的基因功能将作为一种工具来表征对神经元网络的影响，并最终影响大脑功能，从简单的运动行为到复杂的学习特征。此外，转基因小鼠在未来应服从高通量化学/小分子库筛选，以确定药物干扰的退化过程。从蝇筛中出现的一个特定基因被选为该方法的原理证明。拟议项目的成功取决于在Leloir研究所（布宜诺斯艾利斯）的两个实验室和哈佛医学院儿童医院的一个实验室之间建立密切的互动关系。研究生、博士后研究员和年轻的研究人员将有机会在哈佛接受培训，以产生、表征和维持转基因小鼠。这些知识肯定会提高外国机构开发新的神经退行性疾病模型的能力。最终目标是建立长期合作，使我们当地的科学界更紧密地接触新技术，以研究这一具有挑战性的课题。为了实现这一目标，需要准备完整的RO 1研究提案。公共卫生相关性：年龄是神经退行性疾病的一个主要风险因素，这会造成可怕的人类死亡。随着社会老龄化，神经退行性疾病将变得越来越普遍，这强调了深入了解这些毁灭性疾病的分子机制以及开发特定治疗方法的必要性。

DESCRIPTION (provided by applicant): Age is the major risk factor for neurodegenerative diseases. As society age's neurodegeneration become increasingly common, yet the molecular and cellular mechanisms underlying this complex condition remain largely unknown. The goal of this proposal is to explore novel avenues to investigate mechanisms of neurodegeneration in an unbiased manner. A misexpression screen that takes advantage of the power of Drosophila genetics is used to identify genes that may be involved in late-onset behavioral defects (aging). Novel genes that are thus identified to be involved in late neuronal dysfunction can be then characterized and validated in the Drosophila central nervous system by combining genetics, imaging and behavior. Effects of altered gene function can also be tested and validated in the mouse brain, by retrovirus-mediated expression in neurons of the young adult and aging brain. Cell-autonomous effects emerging from these studies will largely contribute to understanding the specific aspects of neuronal function that are affected by the candidate gene. In parallel, a transgenic mouse model will be built based upon the gene identified in Drosophila. Altered gene function in the mouse brain will serve as a tool to characterize the effects on neuronal networks and, ultimately, on brain function, from simple locomotor behaviors to complex learning traits. In addition, transgenic mice should in the future be amenable to high throughput chemical/ small molecule library screens to identify drugs interfering with the degenerative process. A particular gene that emerged from the fly screen, enabled, has been selected as a proof of principle for the approach. The success of the proposed project relies on building a close interaction among two laboratories at the Leloir Institute (Buenos Aires) and a laboratory at Childrens Hospital, Harvard Medical School. Graduate students, postdoctoral fellows and young investigators will have the opportunity to obtain training at Harvard to generate, characterize and maintain transgenic mice. This know-how will certainly improve the capabilities to develop novel models of neurodegeneration at the foreign institution. The ultimate goal is to establish a long-term collaboration in order to bring our local scientific community in closer contact with novel technologies for research on this challenging topic. To accomplish such goal the preparation of full RO1 research proposal is warranted. PUBLIC HEALTH RELEVANCE: Age is a major risk factor for neurodegenerative diseases, which cause a terrible human toll. As society ages, neurodegenerative diseases will become increasingly common, underscoring the need for an in depth understanding of the molecular mechanisms underlying these devastating diseases, as well as the development of specific treatments.