The Jackson Laboratory Senescence Tissue Mapping Center (JAX-Sen TMC)

项目总结/摘要 杰克逊实验室（JAX）细胞衰老网络小鼠组织绘图中心（JAX-Sen） 代表了多模式的跨学科的努力，借鉴现有的，长期的老龄化研究计划 在JAX，我们作为KAPP-Sen的联盟网站，一个由SenNet资助的人类组织绘图中心，以及JAX的 与UConn Health合作。JAX-Sen是围绕三个核心组织起来的，这些核心嵌套在资源充足的 JAX的老化研究和多组学分析环境。JAX-Sen将分析肾脏中的衰老细胞， 脂肪组织、胎盘、胰腺、心脏和下丘脑，根据其与慢性胰腺炎的临床相关性选择 衰老疾病，JAX-Sen领导团队在这些组织生物学方面的领域专业知识，以及 我们将利用尖端的小鼠资源，包括 多样性远交，它提供了无与伦比的遗传多样性，用于模拟一系列分子衰老 表型，以及表达p16和p21驱动的荧光标记的新的近交系（C57 BL/6 J）转基因小鼠， 允许特定衰老细胞亚群的可视化富集。生物分析核心将应用 选择的组织的多种分析模式（批量和单细胞和单核RNAseq，Visium 空间转录组学，多重抗体成像，多重FISH，成像质谱 包括脂质组学、代谢组学、蛋白质组学、连续切片的3D组织重建），并将重新 在整个项目期间评估这些技术，以确保我们的方法与其他公司的方法保持一致。 我们将继续致力于在SenNet的技术开发工作中最大限度地受益。这些侧写 活性将产生衰老细胞中的生物分子含量的亚细胞分辨率，这对于人类来说是不可能的。 样本，沿着一组扩展的衰老细胞生物标志物。数据分析核心将结合联合收割机强大的 具有可扩展和可重复的科学工作流程的计算能力，以开发和实施网络- 广泛开放的数据和元数据标准。数据分析核心将受益于JAX独特的鼠标研究 通过整合表达数量性状基因座， DO小鼠中的蛋白质数量性状基因座数据和JAX生物信息学资源，例如，小鼠基因组 信息学，小鼠表型数据库，君主倡议。JAX-Sen数据的综合挖掘将导致 新的方法，多模态三维地图重建成像数据，并将产生一个重要的资源， 人类衰老细胞数据的SenNet解释和富集。最后，行政核心将提供 加强对项目进展的监督，并在内部培养一种协作、动态科学交流的文化。 JAX-Sen。它还将通过合作活动最大限度地提高JAX-Sen在该联盟中的参与度， 帮助优化数据生成活动并创造新的研究协同效应。这样做，JAX-Sen将帮助 实现SenNet的目标，生成前所未有的小鼠衰老细胞图谱和新的 用于人体分析和治疗应用。

PROJECT SUMMARY/ABSTRACT OVERALL The Jackson Laboratory (JAX) Cellular Senescence Network Mouse Tissue Mapping Center (JAX-Sen) represents a multi-modal interdisciplinary effort that draws upon existing, longstanding aging research programs at JAX, our role as a consortium site of KAPP-Sen, a funded SenNet human Tissue Mapping Center, and JAX’s close collaboration with UConn Health. JAX-Sen is organized around three cores nested in the well-resourced environment for aging research and multi-omics profiling at JAX. JAX-Sen will profile senescent cells in kidney, adipose tissue, placenta, pancreas, heart, and hypothalamus, selected for their clinical relevance to chronic diseases of aging, the domain expertise of the JAX-Sen leadership team in the biology of these tissues, and the overlap of four of the tissues with KAPP-Sen. We will leverage cutting-edge mouse resources including the Diversity Outbred, which offers unparalleled genetic diversity for modelling a range of molecular senescence phenotypes, and new inbred (C57BL/6J) transgenic mice that express p16 and p21 driven fluorescent tags to allow visualization enrichment for specific senescent cell subsets. The Biological Analysis Core will apply a multitude of analytical modalities to selected tissues (bulk and single cell and single nucleus RNAseq, Visium spatial transcriptomics, multiplexed antibody-based imaging, multiplexFISH, imaging mass spectrometry including lipidomics, metabolomics, proteomics, 3D tissue reconstruction from serial sections), and will re- evaluate these technologies throughout the project period to ensure our approaches align with those of other centers and that we maximally benefit from the technology development efforts in SenNet. These profiling activities will yield subcellular resolution of biomolecular content in senescent cells not possible with human samples, along with an expanded set of senescent cell biomarkers. The Data Analysis Core will combine robust computational capability with scalable and reproducible scientific workflows to develop and implement Network- wide open data and metadata standards. The Data Analysis Core will benefit from JAX’s unique mouse research resources to establish the diversity of senescence by integrating with expression quantitative trait locus and protein quantitative trait locus data in DO mice and JAX bioinformatics resources, e.g., Mouse Genome Informatics, Mouse Phenome Database, Monarch Initiative. The integrative mining of JAX-Sen data will lead to novel methods for multi-modal 3D map reconstruction from imaging data and will yield an important resource for SenNet interpretation and enrichment of human senescent cell data. Finally, the Administrative Core will provide strong oversight of project progress and nurture a culture of collaborative, dynamic scientific exchange within JAX-Sen. It will also maximize JAX-Sen’s engagement in the consortium through collaborative activities that will help optimize data generation activities and create new research synergies. In so doing, JAX-Sen will help achieve the goal of SenNet to generate a unprecedented atlas of mouse senescent cells and new biomarkers of senescence for human analysis and therapeutic application.