Investigating Genes and Pathways Associated With Longevity and Neurodegenerative Disease

研究与长寿和神经退行性疾病相关的基因和通路

• 批准号: 10534528
• 负责人: MEGAN MAIR
• 金额: $ 4.68万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-03 至 2024-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534528
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Apolipoprotein E; Behavioral Assay; Bioinformatics; Biological; Biological Assay; Biological Models; Brain; Candidate Disease Gene; Categories; Centenarian; Characteristics; Computational Biology; Coupling; Data; Data Set; Databases; Dementia; Development; Disease; Disease Resistance; Disease model; Drosophila genus; Elderly; Evaluation; Evolution; Gene Expression; Gene Mutation; Gene Proteins; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Screening; Genetic Transcription; Genetic study; Health; Histologic; Human; Human Genome; Huntington Disease; Individual; Investigation; Life; Link; Literature; Longevity; Modeling; Molecular; Multiomic Data; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Onset of illness; Parkinson Disease; Pathogenesis; Pathology; Pathway Analysis; Pathway interactions; Performance; Phenotype; Play; Population; Process; Property; Proteomics; Publishing; Resistance; Risk Factors; Robotics; Role; Series; System; Systems Biology; Therapeutic; Time; Validation; Variant; aging brain; aging population; brain health; cell type; diet and exercise; disease phenotype; disorder risk; experience; fly; genetic variant; genome wide association study; healthspan; high risk; improved; improved functioning; in vivo; insight; longevity gene; neuroprotection; novel; preservation; prevent; resilience; tool; transcriptomics

Project Summary Aging is the single largest risk factor in the development of neurodegenerative diseases. An interesting characteristic of this link between aging and neurodegeneration is that populations predisposed to long lifespan appear to be able to delay or avoid the development of neurodegenerative disease entirely. I hypothesize that genes which modulate longevity can also confer neuroprotection, and that those genes protective against neurodegenerative pathologies can also extend healthy brain function during the process of aging. In Aim 1, I will identify which genes implicated in lifespan extension also ameliorate neurodegenerative disease phenotypes. Utilizing a high-throughput robotic behavioral assay system in concert with the genetic tractability of the Drosophila model, the Botas lab has compiled a neuroprotective gene dataset of over 1200 genes that play protective roles in the neurons of Drosophila models of Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease. I have also leveraged data from gene perturbation studies in numerous model organisms documented in the literature to construct a network of evolutionarily-conserved lifespan extending genes. Human longevity data will be integrated into this network using published genome-wide association and centenarian variant data. I will overlay this network with data from our neuroprotective gene dataset to identify genes that both extend lifespan and ameliorate neurodegenerative disease phenotypes. Then, gene set enrichment tools will be used to characterize functional pathways in the network and to identify those related to neuroprotection. Using genes within these pathways, and genes directly interacting with known neuroprotective variants, I will then validate whether other longevity genes are neuroprotective in the context of disease. I will utilize Drosophila models of neurodegenerative diseases to characterize whether alteration of these genes in neurons improves disease-related phenotypes using a sensitive high-throughput neuronal performance assay system. In Aim 2, I will identify whether genes that are protective in disease contexts can improve neuronal and/or glial health during aging. First, I will utilize cross-sectional transcriptomic and proteomic time-series datasets from the brains of flies, mice, and humans to characterize expression changes in the brain that occur with age and disease conserved across evolution. Overlaying this data with our large database of neuroprotective genes, I will identify changes in the brain that may play a protective role in preserving brain health or increase risk of disease onset. I will then use our large-scale in vivo assay system to determine if manipulating the expression of genes associated with aging or neuroprotection against disease improve the function of glia or a specific neuronal subtype during aging. I will use pathway enrichment tools to determine potential mechanisms by which genes that improve neuronal/glial health with age function. When this study is complete, it will deepen our understanding of the biological link between longevity and resilience/resistance to neurodegeneration and provide a pathway to potential therapeutics that can protect the aging brain against disease.

项目摘要 衰老是神经退行性疾病发展的最大风险因素。一个有趣 衰老和神经退化之间联系的一个特点是， 似乎能够延迟或完全避免神经退行性疾病的发展。我假设 调节寿命的基因也可以赋予神经保护作用，而那些保护寿命的基因， 神经退行性病变也可以在衰老过程中延长健康的脑功能。在目标1中， 将确定哪些与延长寿命有关的基因也能改善神经退行性疾病 表型利用高通量机器人行为分析系统与遗传易处理性 在果蝇模型中，Botas实验室编制了一个包含1200多个基因的神经保护基因数据集， 在阿尔茨海默氏病、帕金森氏病的果蝇模型的神经元中起保护作用， 亨廷顿氏病。我还利用了许多模式生物的基因扰动研究数据 在文献中记录了构建进化上保守的寿命延长基因的网络。人类 长寿数据将被整合到这个网络使用已发表的全基因组关联和百岁老人 变量数据我将用我们的神经保护基因数据集的数据覆盖这个网络，以识别 都能延长寿命并改善神经退行性疾病的表型。然后，基因组富集工具 将用于表征网络中的功能通路，并识别与神经保护相关的通路。 利用这些通路中的基因，以及与已知的神经保护变体直接相互作用的基因，我将 然后验证其他长寿基因是否在疾病背景下具有神经保护作用。我会利用果蝇 神经退行性疾病的模型，以表征神经元中这些基因的改变是否改善 疾病相关的表型，使用灵敏的高通量神经元性能测定系统。在目标2中，我 将确定在疾病背景下具有保护作用的基因是否可以改善神经元和/或神经胶质细胞的功能。 衰老期间的健康首先，我将利用来自美国的横截面转录组学和蛋白质组学时间序列数据集。 果蝇、小鼠和人类的大脑，以表征随着年龄的增长而发生的大脑表达变化， 疾病在进化过程中是保守的将这些数据与我们的大型神经保护基因数据库叠加， 将识别大脑中可能在保持大脑健康或增加风险方面发挥保护作用的变化。 发病然后，我将使用我们的大规模体内分析系统来确定是否操纵表达 与衰老或对疾病的神经保护相关的基因的表达， 衰老过程中的神经元亚型。我将使用途径富集工具来确定潜在的机制， 基因改善神经元/神经胶质健康与年龄功能。当这项研究完成后，它将加深我们的 了解长寿和恢复力/抗神经变性之间的生物学联系 并提供了一种潜在的治疗方法，可以保护衰老的大脑免受疾病的侵害。