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

项目摘要/摘要总体 杰克逊实验室(JAX)细胞衰老网络小鼠组织图谱中心(JAX-SEN) 代表了一种多模式的跨学科努力，利用了现有的、长期存在的衰老研究计划 在JAX，我们作为Kapp-Sen、一个资助的Sennet人类组织测绘中心和JAX的 与康涅狄格州大学健康学院密切合作。JAX-Sen围绕三个嵌套在资源丰富的 日本宇宙航空研究开发机构的老龄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，因其与慢性疾病的临床相关性而被选择 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 四种组织与卡普-森的重叠。我们将利用尖端鼠标资源，包括 异种繁殖的多样性，为模拟一系列分子衰老提供了无与伦比的遗传多样性 表型，以及表达p16和p21荧光标签的新型近交系(C57BL/6J)转基因小鼠 允许对特定的衰老细胞亚群进行可视化丰富。生物分析核心将应用 对选定组织的多种分析方法(散装和单细胞及单核RNAseq、Viium 空间转录学，多重抗体成像，多重FISH，成像质谱学 包括脂质组学、代谢组学、蛋白质组学、从连续切片进行三维组织重建)，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方法保持一致 我们将最大限度地受益于Sennet的技术开发工作。这些侧写 这些活动将产生衰老细胞中生物分子含量的亚细胞分辨，这在人类是不可能的 样本，以及一组扩展的衰老细胞生物标记物。数据分析核心将结合强健 具有可扩展和可复制的科学工作流的计算能力，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 整合表达数量性状基因座和基因座建立衰老多样性的资源 DO小鼠的蛋白质数量性状基因座数据和JAX生物信息学资源，如小鼠基因组 信息学，老鼠表现组数据库，君主倡议。JAX-Sen数据的综合挖掘将导致 用于从成像数据中重建多模式3D地图的新方法，将为 人类衰老细胞数据的SENet解释和丰富。最后，行政核心将提供 对项目进展进行强有力的监督，并在内部培养协作、充满活力的科学交流文化 贾克斯-森。它还将通过以下合作活动最大限度地提高JAX-Sen在财团中的参与度 帮助优化数据生成活动，创造新的研究协同效应。在此过程中，JAX-Sen将提供帮助 实现Sennet的目标，生成史无前例的小鼠衰老细胞图谱和新的 人体衰老分析和治疗应用。

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.