Investigating Genes and Pathways Associated With Longevity and Neurodegenerative Disease

项目摘要 衰老是神经退行性疾病发展的单一最大风险因素。一个有趣的故事 衰老和神经退化之间的这种联系的特点是，人口容易长寿 似乎能够完全延缓或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提供神经保护，而这些基因可以防止 神经退行性病变也可以在衰老过程中延长健康的大脑功能。在目标1中，我 将确定哪些基因与延长寿命有关，也可以改善神经退行性疾病 表型。利用高通量机器人行为测试系统与遗传可操纵性相协调 对于果蝇模型，Botas实验室汇编了一个包含1200多个基因的神经保护基因数据库，这些基因 对阿尔茨海默病、帕金森氏病果蝇模型神经元起保护作用 亨廷顿氏病。我还利用了许多模型生物的基因扰动研究数据。 文献中记载了构建进化保守的延长寿命基因网络的方法。人类 长寿数据将使用已公布的全基因组关联和百岁老人整合到这个网络中 变量数据。我将用我们的神经保护基因数据库中的数据覆盖这个网络，以识别 两者都能延长寿命并改善神经退行性疾病的表型。然后，基因集丰富工具 将被用来表征网络中的功能通路，并识别那些与神经保护相关的通路。 利用这些途径中的基因，以及直接与已知的神经保护变体相互作用的基因，我将 然后验证其他长寿基因在疾病背景下是否具有神经保护作用。我会利用果蝇 神经退行性疾病模型以表征神经元中这些基因的改变是否改善 使用灵敏的高通量神经元性能分析系统进行疾病相关表型分析。在目标2中，我 将确定在疾病背景下具有保护性的基因是否可以改善神经元和/或神经胶质细胞 在衰老中保持健康。首先，我将利用横截面转录和蛋白质组时间序列数据集 苍蝇、老鼠和人类的大脑，以表征大脑中随着年龄和年龄的变化而发生的表达变化 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进行叠加，我 将确定大脑的变化，这些变化可能在保护大脑健康方面发挥保护作用，或增加 疾病发作。然后我将使用我们的大规模体内测试系统来确定是否操纵表达 与衰老或疾病的神经保护相关的基因改善神经胶质细胞的功能或特定的 衰老过程中的神经元亚型。我将使用途径丰富工具来确定潜在的机制， 随着年龄的增长，改善神经元/神经胶质健康的基因。当这项研究完成后，它将深化我们的 了解长寿与神经退行性变韧性/抵抗力之间的生物学联系 并提供了一种潜在的治疗方法，可以保护老化的大脑免受疾病的侵袭。

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.