Cross-Species Analysis to Identify Conserve Longevity-Related Pathways and Putative Drug Targets

跨物种分析以确定与长寿相关的途径和假定的药物靶点

• 批准号: 10223817
• 负责人: Daniel Spencer Evans
• 金额: $ 17.3万
• 依托单位: TRANSLATIONAL GENOMICS RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223817
• 关键词: Aging; Biochemical Pathway; Biological; Biological Assay; Biomedical Research; Birds; Blood; Brain; Collaborations; DNA Sequence; Data; Data Analyses; Data Set; Disease; Distant; Drug Targeting; Ensure; Exhibits; Feasibility Studies; Gene Proteins; Genes; Genome; Grant; Health; Heart; Human; Individual; Intervention; Investments; Laboratories; Liver; Longevity; Mammals; Mediating; Methodology; Methods; Mind; Molecular; Molecular Analysis; Morbidity - disease rate; Mus; Muscle; Nucleotides; Parents; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Phylogenetic Analysis; Phylogeny; Physiological; Process; Proteome; Public Domains; Publishing; Research; Research Design; Research Project Grants; Resources; Skin; Source; System; Testing; Tissue Sample; Tissues; Validation; Variant; Work; Yeasts; age related; analytical method; base; data management; fly; insight; molecular phenotype; multiple omics; novel; reference genome; tool; transcriptome; validation studies

ABSTRACT. CROSS-SPECIES ANALYSIS TO IDENTIFY CONSERVED LONGEVITY-RELATED PATHWAYS AND PUTATIVE DRUG TARGETS Despite the massive investment in genomically-guided, and general `omics-based', biomedical research, few studies have generated insights into factors that contribute to health and longevity that can modulated pharmacologically to sustain health and extend longevity. This is clearly due to the number and complexity of factors contributing to longevity. We believe one strategy for identifying factors that unequivocally contribute to longevity is to identify evolutionarily conserved genes and pathways across species that contribute to the pronounced variation in lifespan different species exhibit. However, which species to consider in such analyses, as well as which assays to exploit, are open questions, as is the whether or not aging processes in some distant species (e.g., yeast, worms and flies), given overt physiological differences between them and humans, may not capture genes and pathways relevant to human longevity. With this in mind, we proposed that the best approach to identifying conserved longevity-related genes, pathways and drug targets would involve interrogating as many molecular phenotypes as possible across a very broad range of warm-blooded vertebrate species (i.e. mammals and birds) exhibiting a wide range of lifespans. This will ensure adequate variation is lifespan can be assessed at both the phenotypic and molecular level in species more likely to harbor aging and longevity-related processes consistent with those in humans. However, such an approach would require developing analytical methodology that would accommodate relevant evolutionary phenomena, such as overt DNA sequence differences among genes mediating the expression of different molecular phenotypes, controlling for phylogenetic relationships among species, and identifying and characterizing orthologous relationships among relevant genes and proteins to put into context the relevance of any findings to humans and other species. We propose characterizing the molecular landscape of 60 widely divergent species exhibiting substantial variation in lifespan in at least 5 tissues of relevance to aging and longevity (muscle, heart, liver, brain, skin) in a coordinated effort with the research team associated with the parent UH2/UH3 grant. We will exploit the availability of reference genomes for each of these species, or seek to develop reference genomes where needed, to facilitate analyses. We will also develop novel analytical methods, leverage tools and data from the public domain for more comprehensive analyses, and focus on the relevance of our findings to studies involving humans. These proposed studies are some of the first to champion the notion that the `triangulation' of disparate scientific studies and discoveries, i.e., the attempt to unify results from different study designs based on their biological coherence, is the optimal way to advance identification of longevity-related conserved genes, pathways and targets for longevity-enhancing, geroprotective drugs of relevance to humans.

抽象的。跨物种分析以确定与长寿相关的保守物种 途径和假定的药物靶点 尽管在基因组引导和一般“基于组学”的生物医学研究方面进行了大量投资，但很少有 研究深入了解了有助于健康和长寿的因素，这些因素可以通过调节来实现 药理学上维持健康和延长寿命。这显然是由于其数量和复杂性 有助于长寿的因素。我们相信一种策略可以识别明确有助于 长寿是为了识别物种间进化上保守的基因和途径，这些基因和途径有助于 不同物种的寿命表现出明显的差异。然而，在这种情况下应考虑哪些物种 分析以及利用哪些检测方法都是悬而未决的问题，就像衰老过程是否存在一样 一些遥远的物种（例如酵母、蠕虫和苍蝇），考虑到它们之间存在明显的生理差异 人类，可能无法捕获与人类长寿相关的基因和途径。考虑到这一点，我们提出 识别保守的长寿相关基因、通路和药物靶点的最佳方法是 涉及在非常广泛的温血动物中询问尽可能多的分子表型 脊椎动物物种（即哺乳动物和鸟类）表现出广泛的寿命。这将确保足够的 变异是指寿命可以在物种的表型和分子水平上进行评估。 具有与人类一致的衰老和长寿相关过程。然而，这样的做法 需要开发能够适应相关进化现象的分析方法， 例如介导不同分子表达的基因之间明显的DNA序列差异 表型，控制物种之间的系统发育关系，以及识别和表征 相关基因和蛋白质之间的直系同源关系，以将任何发现的相关性纳入背景 对人类和其他物种。我们建议描述 60 种截然不同的分子景观 至少 5 个与衰老和长寿相关的组织的寿命表现出显着差异的物种 （肌肉、心脏、肝脏、大脑、皮肤）与父母相关的研究团队协调努力 UH2/UH3 补助金。我们将利用每个物种的参考基因组的可用性，或寻求 在需要时开发参考基因组，以促进分析。我们还将开发新颖的分析方法 方法，利用公共领域的工具和数据进行更全面的分析，并重点关注 我们的研究结果与涉及人类的研究的相关性。这些拟议的研究是第一个 拥护这样一种观念，即对不同的科学研究和发现进行“三角测量”，即试图 根据生物学一致性来统一不同研究设计的结果，是推进研究的最佳方式 鉴定与长寿相关的保守基因、延长寿命的途径和靶标， 与人类相关的老年保护药物。

项目成果

Artificial Intelligence and Personalized Medicine.

人工智能和个性化医疗。

• 发表时间: 2019
• 作者: Schork; Nicholas J
• 通讯作者: Nicholas J

Accuracy of haplotype estimation and whole genome imputation affects complex trait analyses in complex biobanks.

单倍型估计和全基因组插补的准确性影响复杂生物库中的复杂性状分析。

• 发表时间: 2023-01-26
• 影响因子: 5.9
• 作者: Appadurai, Vivek;Bybjerg;Krebs, Morten Dybdahl;Rosengren, Anders;Buil, Alfonso;Ingason, Andrés;Mors, Ole;Børglum, Anders D;Hougaard, David M;Nordentoft, Merete;Mortensen, Preben B;Delaneau, Olivier;Werge, Thomas;Schork, Andrew
• 通讯作者: Schork, Andrew

Distinct longevity mechanisms across and within species and their association with aging.

物种间和物种内独特的长寿机制及其与衰老的关系。

• 发表时间: 2023-06-22
• 影响因子: 64.5
• 作者: Tyshkovskiy, Alexander;Ma, Siming;Shindyapina, Anastasia V;Tikhonov, Stanislav;Lee, Sang;Bozaykut, Perinur;Castro, José P;Seluanov, Andrei;Schork, Nicholas J;Gorbunova, Vera;Dmitriev, Sergey E;Miller, Richard A;Gladyshev, Vadim N
• 通讯作者: Gladyshev, Vadim N