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Cytoplasmic chromatin fragments in cell senescence - novel mechanisms and interventions

细胞衰老中的细胞质染色质片段——新机制和干预措施

基本信息

批准号：
10185176
负责人：
PETER D. ADAMS
金额：
$ 62.86万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
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：
2021-05-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10185176
关键词：
Address Aging Autophagocytosis Binding Proteins Cell Aging Cell Nucleus Cells Cellular Stress Characteristics Chromatin Chronic Cytoplasm DNA DNA Damage DNA Double Strand Break DNA Repair Pathway Data Development Disease Double Strand Break Repair Event Excision Gamma-H2AX Genomic DNA Glycolysis Histones Human Hypoxia Inducible Factor Impairment Inflammation Inflammatory Intervention Link Longevity MAPK8 gene Malignant Neoplasms Mediating Metabolism Mitochondria Modeling Molecular N-terminal Nuclear Pathway interactions Pharmaceutical Preparations Pharmacology Phenotype Phosphotransferases Premalignant Cell Process Reactive Oxygen Species Recycling Role Signal Transduction Source Stains Testing Tissues Toxic effect Transcription Coactivator Tumor Suppression Up-Regulation age effect aged base cell injury combat genome integrity healthy aging histone modification immune clearance in vivo inhibitor/antagonist novel nuclease p53-binding protein 1 preservation prevent response senescence sensor trafficking transcription factor tumor

项目摘要

PROJECT SUMMARY Cellular senescence is a cause of cell and tissue aging. Senescence is caused by a range of cellular stresses and characterized by an irreversible proliferation arrest and a potent pro-inflammatory phenotype, the senescence-associated secretory phenotype (SASP). Senescence-associated proliferation arrest and SASP cooperate in tumor suppression, by arresting proliferation of damaged pre-malignant cells and promoting immune clearance of the damaged cells. However, over the longer term, as a source of chronic inflammation, SASP also promotes tissue aging and disease. Consequently, there is currently much effort devoted to development of pharmacologic approaches to eliminate senescent cells to promote healthy aging. However, these so-called senolytic drugs tend to show unwanted toxicities. An alternative, perhaps less toxic approach, is to use senomorphic drugs to specifically inhibit the pro-aging SASP. Importantly, inhibition of SASP does not necessarily impair the tumor suppressive role of senescence. On the contrary, elimination of SASP can prevent cancer. Hence, it is important to define the mechanism of SASP activation, because its inhibition may be an approach to combat the pro-aging effects of senescent cells. Recently, we showed that senescent cells shed fragments of nuclear chromatin into the cytoplasm, cytoplasmic chromatin fragments (CCF), via a nucleus-to-cytoplasmic blebbing process. CCF are very strongly positive for a DNA damage marker, phosphorylated histone γH2AX. Formation of CCF depends upon a novel manifestation of the cellular recycling process autophagy, specifically nuclear autophagy. CCF signal through cytoplasmic DNA sensors to activate NFκB, the major transcriptional activator of SASP. Most recently, we have defined an unanticipated upstream trigger of CCF and SASP, namely dysfunctional mitochondria in senescent cells. Dysfunctional mitochondria are themselves already linked to chronic inflammation and aging. We hypothesize that nuclear expulsion of CCF harboring DNA double strand breaks is a mechanism for senescent cells with impaired DNA repair pathways to decrease the intranuclear load of toxic DNA double strand breaks. We also hypothesize that dysfunctional mitochondria trigger autophagy-dependent formation of CCF in senescent cells by retrograde mitochondria-to-nucleus signaling, involving JNK kinase and the transcription factors Hypoxia Inducible Factor 1a (HIF1a), the “JNK-CCF” and “HIF-CCF” pathways, respectively. Delineation of the JNK-CCF and HIF-CCF pathways and their interactions will provide new opportunities to intervene to suppress chronic inflammation driven by SASP in vivo, thereby potentiating healthy aging and longevity.

项目总结