Integrative Multi-Scale Systems Analysis of Gene-Expression-Driven Aging Morbidity - Supplement

基因表达驱动的衰老发病率的综合多尺度系统分析 - 补充

• 批准号: 10600507
• 负责人: Thomas Stoeger
• 金额: $ 3.47万
• 依托单位: NORTHWESTERN 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 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10600507
• 关键词: Address; Age; Aging; Bioethics; Biology of Aging; Buffers; COVID-19; Cell physiology; Cellular Stress; Cellular biology; Clinical; Clinical Data; Collaborations; Data; Data Science; Data Scientist; Data Set; Ensure; Failure; Foundations; Functional disorder; Gene Expression; Gene Expression Profiling; Genes; Genome; Grant; Health; Homeostasis; Immune; Immunologist; Impairment; In Vitro; Individual; Inflammatory Response; Influenza; Influenza A virus; Laboratories; Learning; Length; Link; Lung infections; Machine Learning; Macromolecular Complexes; Mentors; Molecular; Morbidity - disease rate; Mus; Nature; Organ; Pathway interactions; Patients; Phase; Postdoctoral Fellow; Predisposition; Process; Proteome; Publishing; Regulation; Research; Research Personnel; Running; Scientist; Site; Stimulus; Stress; Supervision; Systems Analysis; Techniques; Testing; Time; Training; Transcript; Up-Regulation; Viral Pneumonia; Work; Writing; age related; aged; biological adaptation to stress; in vivo Model; insight; multiple chronic conditions; multiple omics; post-doctoral training; proteostasis; resilience; response; skills; stoichiometry; transcriptome; transcriptomics

Project Summary The investigator identified through unbiased analysis of own and published datasets that during aging, and infection of the lung with influenza A, there is a progressive imbalance in the transcript levels encoded by short genes relative to those encoded by long genes (revision currently under review in Nature Aging). Failure of gene expression homeostasis impacts the rheostatic ability of almost all cellular processes implicated in aging impairing organ function, particularly in response to systemic stress. Transcriptome imbalance could account for manifestations of aging through several potential mechanisms, including: 1) The dysregulation of individual genes, 2) A dysregulation of the stoichiometry of macromolecular complexes, 3) A relative upregulation of short early-response inflammatory genes, 4) A breakdown of the coordination between molecular pathways and processes encoded by genes of different lengths and 5) A reduction in the capacity of protein homeostasis and cell stress responses to respond towards external stimuli by sequestering its activity toward a buffering of transcriptome imbalance. The investigator will test the hypothesis that during aging transcriptome imbalance globally interferes with the functions encoded by the genome and contributes to the loss of resilience in older individuals. To address this fundamental question, he suggested mammalian ex vivo, in vitro, and in vivo models of age-dependent transcriptome imbalance, and machine-learning approaches, but because of COVID-19 related availability refocused on latter and clinical and multi-omic patient data. Reflecting the interdisciplinary character, he will work under the supervision of his main mentor Dr. Amaral, a network scientist and data-scientist, and his co-mentor Dr. Morimoto, a molecular biologist studying protein homeostasis and aging. Further marking his transition to independence, he will be mentored by Dr. Budinger, an immunologist studying changes in immune aging, and Dr. McNally, a geneticist and bioinformatician, which is not part of a project grant of his mentors. Aim 1 (K99): To gain mechanistic insight into the origin of transcriptome imbalance in aging. Aim 2 (K99): To determine whether adaptive changes in proteostasis buffer transcriptome imbalance during aging after viral pneumonia. Aim 3 (R00): To causally link transcriptome imbalance to the age-related susceptibility to viral pneumonia. Importantly, the investigator’s mentoring committee has a very strong track record of training postdoctoral fellows in transitioning into independent investigators. He will engage in seminars and learn recent experimental techniques, grant writing, bioethics training, and training on running a laboratory, and obtain additional off-site training on the biology of aging in mice with the purpose to facilitate collaborations. Combining the new skills learned during his K99 mentored phase with his prior expertise in data science and transcriptomics will ensure a strong technical foundation to launch an independent laboratory on gene expression homeostasis in aging and the mechanisms underlying multi-system dysfunction.

项目摘要 研究者通过对自己和发表的数据集进行无偏倚分析，确定了老化期间， 在甲型流感病毒感染肺部后，由短链流感病毒编码的转录物水平存在进行性失衡， 相对于那些由长基因编码的基因（修订目前正在审查自然老化）。基因失效 表达稳态影响几乎所有与衰老有关的细胞过程的抗阻能力 损害器官功能，特别是对全身压力的反应。转录组不平衡可以解释 通过几种潜在的机制表现衰老，包括：1）个体的调节失调 基因，2）大分子复合物的化学计量失调，3）短 早期反应炎症基因，4）分子途径之间协调的破坏， 由不同长度的基因编码的过程和5）蛋白质稳态能力的降低， 细胞应激反应，通过隔离其活性以缓冲 转录组失衡研究者将检验衰老过程中转录组失衡的假设， 全面干扰基因组编码的功能，并导致恢复能力的丧失 在老年人中。为了解决这个基本问题，他建议哺乳动物离体，体外和体内 年龄依赖性转录组不平衡的体内模型和机器学习方法，但由于 COVID-19相关的可用性重新关注后者以及临床和多组学患者数据。反映 跨学科的性格，他将在他的主要导师阿马拉尔博士，网络科学家的监督下工作 和数据科学家，以及他的共同导师森本博士，一位研究蛋白质稳态的分子生物学家， 衰老进一步标志着他的过渡到独立，他将指导博士布丁格，免疫学家 研究免疫老化的变化，麦克纳利博士，遗传学家和生物信息学家，这不是一个 他的导师的项目补助金。目的1（K99）：深入了解转录组失衡的起源机制 在衰老。目的2（K99）：确定蛋白质稳定缓冲液转录组失衡是否发生适应性变化 在病毒性肺炎后的衰老过程中。目的3（R 00）：将转录组失衡与年龄相关的 易患病毒性肺炎。重要的是，调查员的指导委员会有一个非常强大的轨道， 培训博士后研究员转变为独立调查员的记录。他将参加研讨会 并学习最新的实验技术，赠款写作，生物伦理学培训，以及实验室管理培训， 并获得有关小鼠衰老生物学的额外场外培训，以促进合作。 将他在K99指导阶段学到的新技能与他之前在数据科学方面的专业知识相结合， 转录组学将确保建立一个独立的基因表达实验室的强大技术基础 衰老中的内稳态和多系统功能障碍的潜在机制。