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

基本信息

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
项目类别：
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

项目摘要

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。跨物种分析以识别保守的寿命相关途径和推定的药物目标尽管在基因组引导和一般“基础”的生物医学研究上进行了大量投资，但很少研究已经对有助于健康和寿命的因素产生了见解在药理学上以维持健康并延长寿命。这显然是由于数量和复杂性有助于长寿的因素。我们认为，一个策略是确定对因素的因素而毫无疑问的因素寿命是确定跨物种的进化保守基因和途径寿命中明显变化不同的物种。但是，在这种情况下要考虑哪些物种分析以及要利用哪些测定法是开放问题，是否在衰老过程中鉴于它们之间的明显生理差异，一些遥远的物种（例如酵母，蠕虫和苍蝇）人类可能不会捕获与人类寿命相关的基因和途径。考虑到这一点，我们提出了确定保守寿命相关的基因，途径和药物靶标的最佳方法将涉及在非常广泛的温血中询问尽可能多的分子表型脊椎动物（即哺乳动物和鸟类）表现出广泛的寿命。这将确保足够可以在物种的表型和分子水平上评估寿命的变化是寿命与人类中的人相符的港口衰老和寿命相关的过程。但是，这种方法将需要开发可以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的明显DNA序列差异表型，控制物种之间的系统发育关系，并识别和表征相关基因和蛋白质之间的直系关系，以使任何发现的相关性置于上下文对人类和其他物种。我们建议表征60个分子差异的分子景观至少5个与衰老和寿命相关的组织中具有实质寿命的物种（肌肉，心脏，肝脏，大脑，皮肤）与与父母相关的研究团队进行了协调的努力 UH2/UH3赠款。我们将利用这些物种的参考基因组的可用性，或试图寻求在需要时开发参考基因组，以促进分析。我们还将开发新的分析方法，利用公共领域的工具和数据进行更全面的分析，并专注于我们的发现与涉及人类的研究的相关性。这些拟议的研究是第一个倡导这样的观念，即不同科学研究和发现的“三角剖分”，即尝试基于其生物学连贯性的不同研究设计的统一结果，是进步的最佳方法鉴定寿命相关的保守基因，途径和寿命增强的靶标，与人类相关的老年保护药物。