Spatial omics technologies to map the senescent cell microenvironment

空间组学技术绘制衰老细胞微环境图

基本信息

批准号：
10384585
负责人：
Jian Ma
金额：
$ 35.79万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10384585
关键词：
3-Dimensional Adipose tissue Affect Age Biological Brain Cell Aging Cell Culture Techniques Cell Cycle Cell Nucleus Cells Chemotherapy and/or radiation Chronic Collaborations Communities Complex DNA DNA Damage Data Degenerative polyarthritis Detection Diabetes Mellitus Disease Dissociation Feasibility Studies Fibrosis Generations Genes Genetic Transcription Genome Genomics Goals Heart Diseases Heterogeneity Homeostasis Human Imaging technology Immune system Immunologic Surveillance Individual Inflammation Intervention Intrinsic factor Laboratories Link Liver Machine Learning Malignant Neoplasms Maps Measures Methodology Methods Microscopy Modeling Molecular Molecular Conformation Multiomic Data Mus Nerve Degeneration Nuclear Outcome Phase Phenotype Physiology Play Positioning Attribute Production Proteins Proteomics RNA Relapse Resolution Role Sampling Sensitivity and Specificity Series Technology Tissue Banks Tissues Transcript Tumor Suppression United States National Institutes of Health Work base cell type computer framework epigenomics high dimensionality human tissue improved machine learning method multidisciplinary multiple omics new technology novel programs response scale up senescence single cell sequencing tool transcriptome transcriptomics tumor wound healing

项目摘要

Project Summary/Abstract Cellular senescence is a biological program whereby cells exit the cell cycle, typically as a consequence of DNA damage accumulation. After exerting their beneficial effects in young individuals by playing a role in tissue homeostasis, wound healing and tumor suppression, senescent cells are recognized and cleared by the immune system in response to their senescence-associated secretory phenotype (SASP). With age, immunosurveillance becomes increasingly dysregulated, senescent cells accumulate in tissues and their SASP leads to chronic inflammation which has been linked to many age-associated diseases including neurodegeneration, diabetes, osteoarthritis, fibrosis, heart disease and cancer. In addition, radiation and chemotherapy cause the accumulation of senescent cells in both normal and cancer tissues and create a microenvironment which can promote tumor relapse. Hence, methods to characterize the diversity of senescent cells in tissues are critical to improve our understanding of their roles in both normal physiology and disease and to develop more precise and effective senolytic and senostatic interventions. We propose to develop new technologies and integrative solutions to map the spatial epigenomic, transcriptome and proteomic states of senescent cells and their microenvironment in complex tissues. In the UG3 phase, we will develop spatial genomics, transcriptomics and proteomics methodologies to delineate senescent cells in a diverse set of murine tissues, including brain, liver and adipose tissue. We will also perform feasibility studies in a limited number of human samples available through tissue banks and collaborators, and in human cell culture. Our goal is to provide a proof of principle and evaluate the specificity and sensitivity of our proposed tools, technologies and methods (TTM) to identify and characterize the heterogeneity of senescent cells in multiple tissues. In the HG3 phase, we will optimize and expand our methodology to a variety of human tissues obtained from normal samples available from tissue banks, and via collaborations with other SenNet Tissue Mapping Centers (TMCs).

项目摘要/摘要细胞衰老是一个生物学程序，细胞从细胞中退出细胞周期，通常是由于DNA的结果损坏积累。通过在组织中发挥作用，在年轻人中发挥了有益作用后稳态，伤口愈合和肿瘤抑制，衰老细胞被免疫识别和清除系统响应其衰老相关的分泌表型（SASP）。随着年龄的增长，免疫监视越来越失调，衰老细胞积聚在组织中，其SASP导致慢性与许多与年龄相关的疾病有关的炎症，包括神经变性，糖尿病，骨关节炎，纤维化，心脏病和癌症。另外，放射线和化疗导致正常和癌组织中衰老细胞的积累，并建立一个微环境，可以促进肿瘤复发。因此，表征组织中衰老细胞多样性的方法对于提高我们对他们在正常生理和疾病中的作用的理解，并发展更精确以及有效的鼻溶液和鼻孔干预措施。我们建议开发新技术和综合性绘制衰老细胞的空间基因组基因组，转录组和蛋白质组学状态的解决方案及其复杂组织中的微环境。在UG3阶段，我们将开发空间基因组学，转录组学和蛋白质组学方法论可以描绘一组鼠组织中的衰老细胞，包括大脑，肝脏和脂肪组织。我们还将对有限数量的人类样本进行可行性研究通过组织库和合作者以及人类细胞培养。我们的目标是提供原则和评估我们提出的工具，技术和方法（TTM）的特异性和敏感性，以识别和表征多个组织中衰老细胞的异质性。在HG3阶段，我们将优化和将我们的方法扩展到从组织可用的正常样品中获得的多种人体组织银行，并通过与其他Sennet组织映射中心（TMC）合作。