Evaluating diverse technologies for detecting and validating senescent cells in vivo

评估用于检测和验证体内衰老细胞的多种技术

• 批准号: 10376470
• 负责人: Simon Melov
• 金额: $ 33.6万
• 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: 2021-09-22 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376470
• 关键词: Abdomen; Affect; Age; Aging; Antibodies; Aorta; Back; Biological; Biological Markers; Biological Models; Biology; Biopsy; Blood Vessels; Bystander Effect; CDKN2A gene; Cell Aging; Cell Nucleus; Cell Proliferation; Cell surface; Cells; Characteristics; Chronology; Clinical; Communities; Complex; Data; Detection; Development; Disease; Doxorubicin; Elderly; Embryonic Development; Emerging Technologies; Fatty acid glycerol esters; Frequencies; Gene Combinations; Gene Expression; Gene Expression Profiling; Genetic; Genetic Transcription; Genotype; Goals; Growth Factor; Human; Inflammatory; Injections; Lipids; Location; Mainstreaming; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measurable; Microbubbles; Microfluidics; Modeling; Molecular Profiling; Morphology; Mus; Muscle; Muscle Fibers; Nature; Nerve Degeneration; Ovarian; Ovarian Tissue; Ovary; Pathology; Peptide Hydrolases; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Pilot Projects; Production; Proteins; Research Personnel; Sensitivity and Specificity; Skeletal Muscle; Structure; Techniques; Technology; Time; Tissues; Ultrasonography; Validation; Variant; Visualization; age related; aged; antibody conjugate; arteriole; biological adaptation to stress; cell type; chemokine; comparative; contrast enhanced; cytokine; design; digital; high risk; human subject; human tissue; improved; in vivo; innovative technologies; molecular marker; mouse model; nano-string; new technology; novel; prevent; protein expression; reproductive senescence; response; senescence; small molecule; tissue/cell culture; transcriptome; whole genome

PROJECT SUMMARY Single cell profiling has recently exploded into mainstream biology. Single cell profiling has been employed in myriad applications in biology, including multiple diseases, embryonic development, comparative evolutionary studies and aging. Most recently, single cell profiling has informed the phenomena of cellular senescence. This proposal has two phases, UG3 (model systems), and UH3 (human validation). Cellular senescence is a multi-faceted cell fate that arrests cell proliferation, essentially irreversibly, and activates the production and secretion of pro-inflammatory cytokines, chemokines, growth factors, proteases and lipids, termed the Senescence Associated Secretory Phenotype (SASP). The SASP can influence tissue microenvironments, and thus senescent cells can strongly affect tissue function and likely the systemic milieu. Senescent cells increase with age and can drive a growing list of age-related pathologies, ranging from neurodegeneration to cancer, in part through the SASP. There is increasing evidence that there are no universal markers for senescent cells. Instead, senescent cells, while sharing certain characteristics and biomarkers, are remarkably heterogeneous, varying in characteristics with genotype, cell and tissue type, senescence inducer, tissue (and cell culture) microenvironment, and chronology (time after initial senescence induction). While some of the more commonly employed senescence markers have utility in superficially identifying senescent cells de novo, the onus remains on the investigator to demonstrate why a cell should be considered senescent, rather than relying on historical markers such as p16INK4a or p21Cip1. Thus, new technologies designed to identify novel senescent cells and phenotypes are necessary that will require validation both in culture and in tissue. The ultimate goal of this proposal is to develop new technologies to map senescent signatures back to intact human tissue. This goal will enable us to identify and spatially characterize senescent cells in each tissue, uncovering unique markers depending on tissue and cell type. Pilot 1: Identify senescent cells in the mouse vasculature, and determine if they can be detected by ultrasound, and verified in human tissue; Pilot 2: Develop a microphysiologic ex vivo tissue-on-a-chip to model ovarian senescence, and human tissue-tissue interactions via the SASP. These two pilots will use a combination of cell surface markers identified in our initial profiling, and Digital Spatial Profiling (DSP, Nanostring) or Visium (10x) to localize senescent signatures to morphological structures and cells in tissue sections. Our proposal will develop validated markers of senescence in multiple tissues and cell types not previously characterized to deploy these technologies to the broader community.

项目总结