The effect of life span modifying interventions on Alzheimer's Disease in Drosophila and Mice.

寿命改变干预措施对果蝇和小鼠阿尔茨海默病的影响。

• 批准号: 10609394
• 负责人: STEPHEN L HELFAND
• 金额: $ 58.96万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609394
• 关键词: Affect; Aging; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease model; Brain; Chromatin; Chromatin Structure; Circadian Rhythms; Dementia; Dinitrophenols; Drosophila genus; Genetic; Genetic Models; Genome Stability; Geroscience; Goals; Health; Histologic; Human; Intervention; Lamivudine; Link; Longevity; Mammals; Measures; Metabolism; Methyl Ethers; Microscopic; Molecular; Molecular Genetics; Mus; Mutation; Nerve Degeneration; Neurons; Pathway interactions; Persons; Phenotype; Physiological; Retina; Series; Testing; Transgenes; Translating; United States; age related; effective therapy; experimental study; fly; frailty; gene therapy; healthspan; improved; inhibitor; mitochondrial metabolism; mouse model; neurobehavioral; neurobehavioral test; neuropathology; novel; pharmacologic; resilience; response; tau Proteins; therapy development; tool

Project Summary/Abstract: (30 lines maximum) The overall goal of this proposal is to develop genetic and pharmacological interventions that will delay the onset and progression of Alzheimer’s Disease (AD). AD and other Related Dementias (ADRD) affect well over 5 million people in the United States. By mid-century, these numbers are predicted to at least triple. Despite this, there are no effective treatments for these devastating illnesses. The onset and progression of AD has been linked to age-related changes in several critical physiological pathways including cellular and mitochondrial metabolism and genomic stability. We propose the age-related decline in the efficacy of these pathways promotes AD-related neurodegeneration and interventions which improve and stabilize physiological pathways leading to extension of healthy life span will delay the onset and progression of AD. In this proposal we will use the fly and mouse AD models in combination to determine whether potential genetic and pharmacological geroprotectors known to extend life span or health span in flies and mice, through an enhancement of the activity of cellular and mitochondrial metabolism or improvement in genomic stability, delay the onset and progression of neurodegeneration and other AD-related phenotypes in AD models in mice and flies. The goal of these studies is to identify new and novel genetic and pharmacological geroprotectors that can be translated for use in the treatment of AD. We will use specific molecular genetic and pharmacological interventions known to extend life span in flies or to extend health span in mice in the context of molecular genetic models of fly and mouse AD. The effect of each intervention will be evaluated in two different fly AD models (neuronal-specific expression of human Aß42 or human tau) and the 5XFAD mouse AD model. We will test the hypotheses that: (i) genetic interventions known to improve cellular and mitochondrial metabolism or genomic stability and to extend life span in flies or health span in mammals serve as geroprotectors that can delay the onset and progression of the neurodegeneration associated phenotypes in the fly and mouse models of AD and (ii) pharmacological interventions known to improve cellular and mitochondrial metabolism or genomic stability and extend life span in flies or health span in mammals can delay the onset and progression of the neurodegeneration associated phenotypes in the fly and mouse AD models. We will determine whether these interventions delay the onset and progression of a series of AD-related neurodegeneration phenotypes including: (i) decline in whole organismal health (life span in flies, frailty in mice); (ii) loss of neurobehavioral robustness or resilience (mobility and circadian rhythms in flies, a series of neurobehavioral tests in mice); (iii) microscopic histological examination of neurodegeneration in the brain and the retina of flies and gross and microscopic neuro-pathological examination of the relevant regions of the mouse brain; and (iv) molecular changes in mice.

项目摘要/摘要：（最多30行） 该提案的总体目标是开发遗传和药物干预措施，以延迟 阿尔茨海默氏病（AD）的发作和进展。 AD和其他相关痴呆症（ADRD）影响良好 在美国，超过500万人。到本世纪中叶，这些数字至少被预测为三倍。尽管 这是对这些毁灭性疾病的有效治疗方法。广告的发作和进展 与年龄相关的几种关键生理途径的变化有关，包括细胞和线粒体 代谢和基因组稳定性。我们提出了这些途径效率与年龄相关的下降 促进与广告相关的神经变性和干预措施，从而改善和稳定物理途径 导致健康寿命的扩展将延迟AD的发作和进展。在此提案中，我们将使用 苍蝇和小鼠广告模型结合起来，以确定潜在的遗传和药理 通过增强活动，已知可以延长苍蝇和小鼠的寿命或健康跨度的geroprotector 细胞和线粒体代谢或基因组稳定性的改善，延迟发作和进展 在小鼠和果蝇中，AD模型中的神经变性和其他与AD相关的表型。这些研究的目标 是识别可翻译以在 AD的处理。 我们将使用已知延长寿命的特定分子遗传和药物干预措施 在苍蝇和小鼠AD的分子遗传模型的背景下，果蝇或延长小鼠的健康跨度。效果 每种干预措施的两个不同的苍蝇AD模型（人Aß42的神经元特异性表达）将进行评估 或Human Tau）和5XFAD小鼠AD模型。 我们将测试以下假设：（i）已知可以改善细胞和线粒体的遗传干预措施 代谢或基因组稳定性，并延长哺乳动物的苍蝇或健康跨度的寿命为 可以延迟神经退行性相关表型的发作和进展的Geroprotector AD的FLY和小鼠模型以及（II）已知可改善细胞和线粒体的药理干预措施 代谢或基因组稳定性并延长哺乳动物的苍蝇或健康跨度的寿命会延迟发作和 神经变性与苍蝇和小鼠AD模型中相关表型的进展。 我们将确定这些干预措施是否会延迟一系列与AD相关的发作和进展 神经变性表型包括：（i）整个有机健康的下降（苍蝇的寿命，小鼠脆弱）； （ii）神经行为的鲁棒性或弹性的丧失（流动性和昼夜节律，一系列 小鼠的神经行为测试）； （iii）对大脑神经退行性的微观组织学检查 小鼠相关区域的苍蝇，大和微观神经病理学检查的视网膜视网膜 脑; （iv）小鼠的分子变化。