Senescent cell mapping, identification and validation for human somatic and reproductive tissues

人类体细胞和生殖组织的衰老细胞图谱、鉴定和验证

• 批准号: 10684946
• 负责人: Simon Melov
• 金额: $ 223.71万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684946
• 关键词: Advanced Development; Affect; Age; Aging; Atlases; Biocompatible Materials; Biologic Characteristic; Biological; Biological Markers; Biomedical Research; Breast; Budgets; Cell Aging; Cell Proliferation; Cells; Characteristics; Collaborations; Communities; Complement; Complex; Data; Data Analyses; Data Coordinating Center; Development; Distal; Epithelium; Feedback; Follicular Fluid; Gene Expression Profile; Genetic; Goals; Growth Factor; Head; Health; Human; Individual; Institution; Laboratories; Lipids; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Molecular; Molecular Analysis; Mus; Nerve Degeneration; Organism; Output; Ovary; Participant; Pathologic Processes; Pathology; Peptide Hydrolases; Phenotype; Physiological Processes; Physiology; Plasma; Play; Principal Investigator; Process; Proteome; Proteomics; Protocols documentation; Research; Research Personnel; Resource Sharing; Resources; Role; Sampling; Scientist; Skeletal Muscle; Specimen; Structure; Techniques; Technology; Tissues; Urine; Validation; age related; biobank; cell type; chemokine; cytokine; data sharing; design; experience; human tissue; improved; interest; method development; new technology; pharmacologic; reproductive; response; senescence; single cell technology; stressor; technology development; tissue mapping; transcriptome; transcriptomics; web site

OVERALL TMC - PROJECT SUMMARY Cellular senescence is a multi-faceted cell fate that arrests cell proliferation and activates the synthesis and secretion of numerous cytokines, chemokines, growth factors, proteases and lipids, termed the Senescence Associated Secretory Phenotype (SASP). The SASP can influence tissue microenvironments, locally and distally, and thus senescent cells can strongly affect tissue function. Senescent cells (SnCs) increase with age in most vertebrate organisms, including mice and humans, and it is increasingly clear through both genetic and pharmacological manipulations that they can drive a growing list of age-related pathologies, ranging from neurodegeneration to cancer. At present, there are no invariant biomarkers of SnCs and the molecular characteristics of SnCs are remarkably heterogeneous and variable, depending on cell and tissue type, microenvironment, senescence inducer, and timing. Our overall goal is to determine, molecularly and spatially, when and where senescent cells occur in humans, and also how their patterns of gene expression and SASPs vary with tissue physiology and age. These goals are also the goals of the SenNet Consortium. We therefore propose to establish a SenNet tissue mapping center (TMC) comprised of an Administrative Core, Biospecimen Core, Biological Analysis Core and Data Analysis Core. Our proposed TMC will focus on three human tissues (ovary, breast and skeletal muscle) and three biofluids (follicular fluid, plasma and urine). These samples have distinct biological characteristics and cell types (somatic and reproductive; stromal, epithelial and vasculature) that show significant changes with age. All materials are available through established collaborations, subcontractors and/or biobanks (through the Biospecimen Core). Their analyses will include cutting-edge transcriptomic and proteomic techniques that will take advantage of the expertise of several Buck Institute investigators. Our preliminary data show that these tissues and biofluids are amenable to the state-of-the-art technologies proposed in the Biological Analysis and Data Analysis Cores, as well as new technologies proposed in our accompanying Technology Development application (RFA-RM- 21-009). Importantly, our findings will be applicable to many other human tissues and biofluids in order to encompass and complement the overall goals of the larger SenNet Consortium. The Administrative Core will coordinate all aspects of the TMC, from specimen acquisition to analysis, and will oversee and facilitate frequent interactions between the proposed TMC and other investigators, Cores and components of the SenNet Consortium.

总体TMC-项目摘要 细胞衰老是一种多方面的细胞命运，它阻止细胞增殖并激活合成 和分泌大量的细胞因子、趋化因子、生长因子、蛋白酶和脂质，称为 衰老相关分泌表型(SASP)。SASP可以影响组织微环境， 局部和远端，因此衰老的细胞可以强烈地影响组织功能。衰老细胞(SNC) 在包括老鼠和人类在内的大多数脊椎动物中，随着年龄的增长，这一点越来越明显 通过基因和药物操作，它们可以推动与年龄相关的越来越多的 病理，从神经退化到癌症。目前尚无不变的SNCs生物标志物。 而且SNCs的分子特征是显著的异质性和多样性，取决于细胞和 组织类型、微环境、衰老诱导剂和时间。我们的总体目标是从分子上确定 在空间上，人类衰老细胞发生的时间和地点，以及它们的基因模式 随着组织生理学和年龄的不同，其表达和SASP也不同。这些目标也是Sennet的目标 财团。因此，我们建议建立一个由以下人员组成的Sennet组织映射中心(TMC) 管理核心、生物分析核心、生物分析核心和数据分析核心。我们建议的TMC 将重点放在三种人体组织(卵巢、乳房和骨骼肌)和三种生物液体(卵泡液， 血浆和尿液)。这些样本具有不同的生物学特性和细胞类型(体细胞和 生殖、间质、上皮和血管系统)，随着年龄的增长显示出显著的变化。所有材料都是 可通过已建立的合作伙伴、分包商和/或生物库(通过Biosecimen核心)获得。 他们的分析将包括尖端的转录和蛋白质组学技术，这些技术将利用 巴克研究所几名调查人员的专业知识。我们的初步数据显示，这些组织和生物体液 服从于生物分析和数据分析核心中提出的最先进的技术， 以及我们随附的技术开发申请(RFA-RM)中提出的新技术 21-009)。重要的是，我们的发现将适用于许多其他人体组织和生物体液，以便 涵盖和补充更大的Sennet联盟的总体目标。行政核心意志 协调TMC的所有方面，从标本采集到分析，并将监督和促进 拟议的TMC与其他调查员、核心和组成部分之间的频繁互动 Sennet财团。