Identifying Drugs to Treat Age-Dependent Neurodegeneration

确定治疗年龄依赖性神经退行性疾病的药物

• 批准号: 8058888
• 负责人: KIM D. FINLEY
• 金额: $ 66.13万
• 依托单位: EXPRESSION DRUG DESIGNS, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058888
• 关键词: Acute; Address; Adult; Adverse effects; Affect; Age; Aging; Agreement; Alzheimer' s Disease; Autophagocytosis; Behavior; Biological Assay; Biological Models; Cell Aging; Chronic Disease; Circadian Rhythms; Consensus; Defect; Development; Disease; Drosophila genus; Effectiveness; Employee Strikes; Excision; Exposure to; Eye; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Genetic; Goals; Health; Human; Hydrogen Peroxide; Immunosuppression; Individual; Life; Longevity; Lysosomes; Maintenance; Memory impairment; Methods; Mitochondria; Modification; Molecular; Molecular Profiling; Mus; Mutation; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Neurophysiology - biologic function; Nuclear; Oxidative Stress; Parkinson Disease; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Physiology; Plants; Play; Population; Process; Proteins; Reactive Oxygen Species; Recycling; Regulation; Research; Resistance; Role; Screening procedure; Services; Signal Pathway; Sirolimus; Sleep; Stem cells; Techniques; Testing; Therapeutic; Time; Tissues; Ubiquitin; Visual system structure; Work; Yeasts; age related; aged; cytotoxic; design; dosage; drug testing; effective therapy; fly; genetic analysis; in vivo; in vivo Model; interest; kinase inhibitor; multicatalytic endopeptidase complex; nervous system disorder; neuroprotection; normal aging; novel; novel therapeutics; polyglutamine; polyphenol; protective effect; protein aggregate; protein misfolding; protein profiling; relating to nervous system; senescence

DESCRIPTION (provided by applicant): Defining the molecular mechanism that leads to cellular aging and neural degeneration has proven to be difficult. Many types of damage are thought to contribute to senescence and neural degeneration and include mitochondrial and nuclear DNA mutations, protein misfolding, aggregate formation, reactive oxygen species (ROS), and stem cell senescence. However, a consensus has not yet developed as to which mechanism plays a causal role in aging. Indeed, each tissue may have a select set of processes, or "Achilles' heel" that further exacerbated cellular decline. In the nervous system there is an agreement that mitochondrial senescence, the accumulation of ROS-dependent damage and the formation of protein aggregates or inclusion containing ubiquitin are involved with the most human neurological disorders, such as Alzheimer's and Parkinson's disease. There is a growing understanding that the autophagy pathway is involved with maintaining the mature nervous system by facilitating the removal of cellular damage and protein aggregates. The pathway is highly conserved and we found that expression profiles of autophagy genes show a significant decrease in the aging Drosophila CNS. At the same time, markers of cellular damage and aggregates, such as insoluble ubiquitinated aggregates (IUP), show a dramatic increase. Genetic analysis also shows that mutations in key genes significantly shorten adult lifespans (35 to 60%) and cause progressive neural defects that share striking similarities to those seen with Alzheimer's and other neurodegenerative disorders. Of greater significance is our observation that enhancing autophagy in the aging nervous system suppresses the accumulation of cellular damage (IUP) and significantly extends adult life spans. This work shows that examining factors that promote healthy neuronal aging can be done using Drosophila as a model system. In this proposal we take advantage of the conserved regulation of autophagy to identify neural protective compounds that enhance the pathway, promote longevity and neural function. This project involves several validated and optimized assays proposed in our original Phase-I application that were designed to identify compounds that enhanced autophagy, suppressed aggregate formation and extend life spans. In Specific Aim 1 an additional assay, which assesses the ability of different treatments to suppress oxidative stress was included. Specific Aim 2 represents an expansion of our drug-testing platform to assess the effectiveness of different compounds to promote neuronal health and function by examining their effect on several adult behaviors that show an age-dependent decline. Specific Aim 3 takes advantage of the conserved regulation of autophgy and other key protective pathways to identify those neural protective compounds that alter gene expression profiles in the aging nervous system. The goal of this proposal is to better understand the role of clearance pathways on aging and to develop in vivo assays that identify drugs that could be used for the treatment of human neurological disorders. PUBLIC HEALTH RELEVANCE: Presently there is no effective treatment for Alzheimer's disease and other age-related disorders that affect millions worldwide. Developing an effective method for validating neural protective compounds would streamline the development of life saving therapies. The research outlined in this proposal used Drosophila to develop several medium-throughput in vivo screening techniques that can identify novel therapeutic compounds for the treatment of aging disorders.

描述（由申请人提供）：确定导致细胞衰老和神经变性的分子机制已被证明很困难。人们认为许多类型的损伤会导致衰老和神经变性，包括线粒体和核DNA突变，蛋白质错误折叠，骨料形成，活性氧（ROS）和干细胞衰老。但是，关于哪种机制在衰老中起因果作用的共识尚未达成共识。实际上，每个组织都可能具有一组精选的过程，或“阿喀琉斯”脚跟，这进一步加剧了细胞的下降。在神经系统中，有一个协议，即线粒体衰老，ROS依赖性损伤的积累以及蛋白质聚集体的形成或含有泛素的纳入蛋白质疾病与最人类的神经系统疾病有关，例如阿尔茨海默氏病和帕克森病。人们越来越了解自噬途径与通过促进细胞损伤和蛋白质聚集体的去除来维持成熟的神经系统有关。该途径是高度保守的，我们发现自噬基因的表达谱显示果蝇衰老的CNS显着降低。同时，细胞损伤和聚集体的标志物（例如不溶性泛素化骨料（IUP））显示出急剧增加。遗传分析还表明，关键基因的突变显着缩短了成年寿命（35至60％），并引起进行性神经缺陷，与与阿尔茨海默氏症和其他神经退行性疾病的突变相似。我们的观察结果更为重要，即增强衰老神经系统中的自噬会抑制细胞损伤（IUP）的积累，并显着延长成人寿命。这项工作表明，可以使用果蝇作为模型系统来检查促进健康神经元衰老的因素。在此提案中，我们利用自噬的保守调节来识别增强途径，促进寿命和神经功能的神经保护化合物。该项目涉及我们原始I期应用程序中提出的几种经过验证和优化的测定，旨在识别增强自噬，抑制的骨料形成并扩展寿命跨度的化合物。在特定目标1中，包括另外的测定法，该测定法评估了不同治疗抑制氧化应激的能力。特定目标2代表了我们的药物测试平台的扩展，以评估不同化合物的有效性，以促进神经元健康和功能，通过检查它们对几种成年行为的影响，这些行为显示出年龄依赖年龄的下降。特定目标3利用自噬和其他关键保护途径的保守调节来识别改变衰老神经系统中基因表达谱的那些神经保护化合物。该提案的目的是更好地了解清关途径在衰老中的作用，并开发体内测定，以鉴定可用于治疗人类神经疾病的药物。 公共卫生相关性：目前尚无对阿尔茨海默氏病和其他影响全球数百万年龄相关的疾病的有效治疗方法。开发一种验证神经保护化合物的有效方法将简化挽救生命疗法的发展。该提案中概述的研究使用果蝇开发了几种中等通量的体内筛查技术，这些技术可以鉴定出用于治疗衰老疾病的新型治疗化合物。