Neural Aging and A Toxicity Assessments, a Fly Pharmacology-Molecular AD Model

神经衰老和毒性评估，苍蝇药理学分子 AD 模型

• 批准号: 10263906
• 负责人: KIM D. FINLEY
• 金额: $ 18.81万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263906
• 关键词: Acute; Address; Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-42; Amyloid beta-Protein; Animal Model; Arctic Regions; Astrocytes; Autophagocytosis; Behavior; Behavioral; Bioinformatics; Cell physiology; Cells; Chronic; Complex; Couples; Craniocerebral Trauma; Defect; Development; Diet; Disease; Disease Progression; Drosophila genus; Effectiveness; Environmental Risk Factor; Exposure to; Foundations; Future; Gene Expression; Genetic; Genetic Transcription; Gerontology; Geroscience; Goals; Human; Immune; Impairment; Incidence; Inflammaging; Inflammation; Inflammatory Response; Intermittent fasting; Intervention; Link; Locomotion; Longevity; Maintenance; Metabolic; Methods; Microglia; Modeling; Molecular; Mus; Natural Immunity; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neuroglia; Neurons; Neurophysiology - biologic function; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Population; Process; Production; Public Health; Reagent; Research; Research Proposals; Risk Factors; Rodent Model; Role; Signal Pathway; Signal Transduction; Sleep; Standardization; Stress; Symptoms; Synapses; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Trauma; Trauma patient; Traumatic Brain Injury; Treatment Protocols; Work; abeta accumulation; age related; aged; amyloid precursor protein processing; base; biological adaptation to stress; cytotoxic; design; dietary; disability; effectiveness evaluation; fly; functional decline; healthspan; healthy aging; human model; in vivo; insight; neural model; neurodevelopment; neuromechanism; new therapeutic target; novel therapeutics; prevent; protective effect; protein aggregation; relating to nervous system; response; response to brain injury; selective expression; signal processing; stroke model; transcriptome sequencing; transcriptomics; trauma exposure; unhealthy lifestyle

Neural Aging and Ab Toxicity Assessments, a Fly Pharmacology-Molecular AD Model Abstract: Human studies have shown that the progressive accumulation of protein aggregates (Aβ42) is key a factor in the development of neurodegenerative disorders, including Alzheimer’s disease (AD). As a result, a significant portion of AD research has since focused on the origin and cytotoxic effects that Aβ42 has on the maintenance, stress responses and functional decline of neurons. However, geroscience studies have highlighted other metabolic, proteolytic, stress response and cell signaling pathways are also closely linked to aging and neurodegenerative processes. It has emerged that AD risk factors include chronic activation of innate immunity (inflammaging) and impaired proteolytic clearance. In addition, AD associated processes like NFkb signaling and APP processing are also involved with neural development and synaptic remodeling. This indicates that a less focus more nuanced geroscience based approach to study AD and potential therapies is required. Our work on gerontology has largely focused on the role of autophagy using an aging Drosophila model. We found that the autophagic capacity of neurons is directly correlated with aggregate formation, stress responses and longevity profiles of Drosophila. Using a fly aging model, we have identified dietary (intermittent fasting, IF) and drug treatment regimens that promote autophagic and neuronal function. This is in part by restoring more youthful gene expression and transcriptional drift variance (TDV) profiles in aged neural tissues. Of particular mechanistic importance was the profound age-related dysregulation of proteolytic components, which was largely suppressed by IF. We developed a second Drosophila model, examining traumatic brain injury (TBI). Using standardized conditions, TBI-treated flies showed conserved pathway changes (autophagy, NFkb), behavioral defects (locomotion, sleep) and molecular alterations known to occur in human trauma patients and in rodent models. We find that aging and the genetic background of adult flies alters TBI responses, as does select drug (J147) or IF treatment. The goal of this application is to take an integrated approach using an AD Drosophila model to examine the impact that in vivo aggregate formation (Aβ42-Arctic) has on the aging or traumatized CNS. The central hypothesis of this proposal is that common protective molecular pathways can be identified using animal models and these unique mechanistic insights can be exploited to develop new therapeutic treatments for complex aging and neurodegenerative disorders. Specific Aim 1 will determine the impact that tissue specific production of Aβ42-Arctic has on the neural aging and TBI dependent phenotypes and longevity profiles of adult Drosophila. In Specific Aim 2, we will use our Drosophila neural aging, trauma and AD models to determine the effectiveness of select diets (IF) and compounds (J147) to delay or suppress phenotypes associated many neural degenerative disorders. Findings from this proposal will be the foundation for future gerosciene studies examining the conserved mechanisms of neural aging and the identification of neuroprotective treatments.

神经老化和抗体毒性评估，一种果蝇药理学-分子AD模型 摘要： 人体研究表明，蛋白质聚集体（Aβ42）的逐渐积累是导致 神经退行性疾病的发展，包括阿尔茨海默病（AD）。因此，一个重要的 AD研究的一部分集中在Aβ42对维持的起源和细胞毒性作用， 应激反应和神经元功能衰退。然而，老年科学研究强调了其他 代谢、蛋白水解、应激反应和细胞信号传导途径也与衰老密切相关， 神经退化过程已经发现AD的危险因素包括先天免疫的慢性激活 （炎症）和受损的蛋白水解清除。此外，AD相关过程如NF kb信号传导 和APP加工也参与神经发育和突触重塑。这指示 需要更少关注更细致的基于老年科学的方法来研究AD和潜在的治疗方法。我们的工作 关于老年学的研究主要集中在使用衰老果蝇模型的自噬作用上。我们发现 神经元的自噬能力与聚集体形成、应激反应和 果蝇的寿命概况。使用苍蝇衰老模型，我们已经确定了饮食（间歇性禁食，IF）和 促进自噬和神经元功能的药物治疗方案。这部分是通过恢复更年轻的 基因表达和转录漂移方差（TDV）的档案在老化的神经组织。特别是机械的 重要的是与年龄相关的蛋白水解组分的严重失调，这在很大程度上是 如果被压制。我们开发了第二个果蝇模型，检查创伤性脑损伤（TBI）。使用 在标准化条件下，TBI处理的果蝇显示出保守的途径变化（自噬，NF kb）， 已知在人类创伤患者和啮齿动物中发生的缺陷（运动、睡眠）和分子改变 模型我们发现成年果蝇的衰老和遗传背景改变了TBI反应，选择药物也是如此。 （J147）或IF治疗。这个应用程序的目标是采取综合的方法，使用AD果蝇 模型，以检查体内聚集体形成（Aβ42-Arctic）对老化或创伤性CNS的影响。 这一建议的中心假设是，共同的保护性分子途径可以确定使用 动物模型和这些独特的机制见解可以用来开发新的治疗方法 治疗复杂的衰老和神经退行性疾病具体目标1将确定组织特异性 Aβ42-Arctic的产生对成年人的神经衰老和TBI依赖性表型和寿命谱有影响 果蝇在具体目标2中，我们将使用我们的果蝇神经老化，创伤和AD模型来确定 选择的饮食（IF）和化合物（J147）延迟或抑制与许多表型相关的表型的有效性 神经退行性疾病本研究的发现将为未来老年科学的研究奠定基础 检查神经老化的保守机制和神经保护治疗的鉴定。