Project 2: Cytoplasmic chromatin fragments (CCF) as a driver of liver cancer and target for intervention during aging

项目2：细胞质染色质片段（CCF）作为肝癌的驱动因素和衰老过程中的干预目标

• 批准号: 10270687
• 负责人: PETER D. ADAMS
• 金额: $ 37.38万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10270687
• 关键词: Acute; Age; Aging; Antitumor Response; Antiviral Agents; Automobile Driving; Autophagocytosis; Benign; Cell Aging; Cell Nucleus; Cell Proliferation; Cells; Cellular Stress; Characteristics; Chromatin; Chronic; Cirrhosis; Cytoplasm; DNA; Data; Diet; Disease; Disease Outcome; Family; Fatty Liver; Fibrosis; Genes; Hepatocyte; Human Characteristics; Immune; Immune checkpoint inhibitor; Immunosuppression; Incidence; Inflammation; Inflammatory; Interferon-alpha; Interferons; Intervention; JNK-activating protein kinase; Knockout Mice; Liver; Malignant neoplasm of liver; Mediating; Molecular; Molecular Profiling; Mus; Mutation; Neoplasms; Oncogenes; Oncogenic; Organism; Pathway interactions; Phenotype; Predisposition; Prevention strategy; Primary carcinoma of the liver cells; Process; Resistance; Risk; Risk Factors; Role; Severities; Signal Pathway; Signal Transduction; Sirolimus; Source; Testing; Tissues; Tumor Suppressor Genes; Up-Regulation; Virus; adaptive immunity; age related; aged; base; cell transformation; chronic liver disease; cytokine; epigenome; genetic manipulation; immune clearance; immunosuppressed; in vivo; indexing; inhibitor/antagonist; liver cancer prevention; mitochondrial dysfunction; mitochondrial metabolism; neoplastic; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; nuclease; prevent; programmed cell death ligand 1; response; senescence; tumor; tumor-immune system interactions; tumorigenesis; tumorigenic

PROJECT SUMMARY – PROJECT 2 The incidences of liver cancer (primarily hepatocellular carcinoma (HCC)) are increasing and disease outcome is poor. Consequently, there is an urgent need for new therapies and preventive strategies. Age is a major risk for HCC and non-alcoholic fatty liver disease (NAFLD). NAFLD is a chronic liver disease that encompasses a progressive range of disorders of increasing severity and risk of HCC, from benign fatty liver (steatosis), to inflammatory non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Aging is accompanied by many molecular, cellular and tissue changes that are candidate drivers of NAFLD and HCC, including the “hallmarks of aging” that are dysregulated with age in diverse tissues and organisms; for example, changes to mitochondria, metabolism, the epigenome, accumulation of senescent cells, inflammation and immune changes. Cell 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). Recently, we showed that in senescent cells, mitochondria dysfunction signals to evict fragments of chromatin from the nucleus into the cytoplasm (cytoplasmic chromatin fragments (CCF)) via a nucleus-to- cytoplasmic blebbing process. CCF are sensed by the anti-viral cytoplasmic DNA sensing apparatus to activate NFkB and the SASP. The SASP of senescent cells includes interferons, a family of cytokines involved in cell intrinsic anti-viral mechanisms, control of cell proliferation, inflammation and adaptive immunity, and tumor suppressive and oncogenic processes. Although SASP and acute IFN signaling have important benefits, chronic SASP and IFN signaling can be detrimental. As a source of chronic inflammation, SASP promotes tissue aging and disease, including liver cancer. Chronic IFN signaling can promote immunosuppression, in part by upregulation of immune checkpoint inhibitors, such as PD-L1. Based on unpublished data, we hypothesize that accumulation of CCF in aged and/or senescent liver hepatocytes drives chronic activation of IFN signaling, expression of IFN target genes and immune checkpoint inhibitors, such as PD-L1. We further hypothesize that this, in turn, generates an immunosuppressed liver microenvironment that is permissive for transformation of old hepatocytes. By antagonizing this immunosuppressive signaling pathway, we hypothesize that several different types of intervention can prevent liver cancer during aging. Completion of these Specific Aims will promote novel interventions to prevent HCC.

项目总结-项目2