Mechanisms of progressive neurodegeneration: combining forward genetic screens in

进行性神经变性的机制：结合正向遗传筛选

• 批准号: 8053114
• 负责人: Maria Fernanda Ceriani
• 金额: $ 3.87万
• 依托单位: FUNDACION INSTITUTO LELOIR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053114
• 关键词: Adult; Affect; Age; Aging; Animal Model; Architecture; Argentina; Behavior; Behavioral; Biological Models; Brain; Candidate Disease Gene; Cells; Cognitive; Collaborations; Communities; Complex; Data; Defect; Development; Diagnostic; Disease; Dominant-Negative Mutation; Down-Regulation; Drosophila genus; Electroporation; Ensure; Family; Family member; Fostering; Future; Generations; Genes; Genetic; Genetic Screening; Goals; Grant; Homeostasis; Hospitals; Human; Image; Impaired cognition; Institutes; Institution; Laboratories; Lead; Learning; Mammals; Mediating; Modeling; Molecular; Molecular Biology; Monitor; Motor; Mus; Mutation; Nature; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Oncogene Deregulation; Pharmaceutical Preparations; Phenotype; Physiology; Play; Postdoctoral Fellow; Premature aging syndrome; Preparation; Process; Protein Family; Research; Research Personnel; Research Proposals; Retroviridae; Risk Factors; Rodent; Rodent Model; Role; Site; Slice; Small Molecule Chemical Library; Societies; Solid; Staging; Structure; Synapses; System; Techniques; Testing; Therapeutic; Training; Transgenic Animals; Transgenic Mice; Transgenic Organisms; aging brain; base; behavior test; embryonic stem cell; fly; gene function; genetic manipulation; graduate student; improved; in utero; in vivo; insight; interest; medical schools; mouse model; neurodegenerative phenotype; new technology; novel; progressive neurodegeneration; public health relevance; research study; retroviral transduction; success; tool; trait; vasodilator-stimulated phosphoprotein; young adult

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.

描述（由申请人提供）：年龄是神经退行性疾病的主要危险因素。随着社会年龄的增长，神经退行性变变得越来越普遍，然而这种复杂情况的分子和细胞机制在很大程度上仍然未知。本提案的目的是探索新的途径，以公正的方式调查神经变性的机制。利用果蝇遗传学的力量，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，通过结合遗传学、影像学和行为学，可以在果蝇中枢神经系统中鉴定和验证与晚期神经元功能障碍有关的新基因。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人和衰老大脑神经元表达进行测试和验证。从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受候选基因影响的神经元功能的特定方面。同时，一个转基因小鼠模型将建立在果蝇基因的基础上。小鼠大脑中基因功能的改变将作为表征对神经网络的影响的工具，并最终表征从简单的运动行为到复杂的学习特征对大脑功能的影响。此外，转基因小鼠将来应该能够适应高通量化学/小分子文库筛选，以识别干扰退行性过程的药物。从苍蝇筛选中出现的一个特殊基因被激活，被选为该方法的原理证明。拟议项目的成功依赖于在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。研究生、博士后和年轻研究人员将有机会在哈佛获得培养、鉴定和维持转基因小鼠的培训。这种技术肯定会提高国外机构开发新型神经变性模型的能力。最终目标是建立长期合作关系，以便使我们当地的科学界更密切地接触新技术，以研究这一具有挑战性的主题。为了实现这一目标，准备完整的RO1研究计划是必要的。