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Role of HDAC7 in senescence-associated inflammation

HDAC7 在衰老相关炎症中的作用

基本信息

批准号：
10241964
负责人：
Karl Nathan Miller
金额：
$ 7.05万
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：
2019
资助国家：
美国
起止时间：
2019-09-12 至 2022-09-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241964
关键词：
Ablation Acute Age Aging Antibodies Autophagocytosis Cell Aging Cell Nucleus Cells ChIP-seq Chromatin Chronic Chronic Disease Co-Immunoprecipitations Communication Complex Cytoplasm DNA DNA Damage Disease Excision Gene Expression Gene Targeting Genetic Growth HDAC7 histone deacetylase Histone Deacetylase Histone Deacetylase Inhibitor Inflammaging Inflammation Inflammatory JNK-activating protein kinase Lamin B1 Link Longevity MAPK8 gene Malignant neoplasm of liver Mass Spectrum Analysis Measures Mediator of activation protein Mitochondria Molecular Mus Mutagenesis Nuclear Pathway interactions Pharmaceutical Preparations Pharmacology Pharmacotherapy Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphoserine Prevention Preventive treatment Primary carcinoma of the liver cells Process Production Protein Dephosphorylation Proteins Reactive Oxygen Species Role Signal Pathway Signal Transduction Site Source Stimulator of Interferon Genes Stress Testing Threonine Tissues Toxic effect Tumor Suppressor Proteins aged chronic liver inflammation cytokine experimental study healthspan healthy aging immune clearance improved in vivo inhibitor/antagonist interest knock-down mitochondrial dysfunction new therapeutic target novel p53-binding protein 1 prevent response senescence side effect stressor therapeutic target tool transcriptome sequencing

项目摘要

PROJECT SUMMARY Cellular senescence is a hallmark of the aging process and contributes to chronic disease vulnerability. Although senescence acts acutely as a tumor suppressor mechanism, chronically it also contributes to inflammation in aged tissue through the senescence-associated secretory phenotype (SASP). Hence, removal of senescent cells in vivo improves healthspan and lifespan, although pharmacological “senolytic” approaches tend to have toxic side effects, likely limiting the utility of senolytics as tools to promote healthy aging. As proof-of-concept for an alternative approach, suppression of SASP in vivo reduces chronic liver inflammation and delays onset of hepatocellular carcinoma. Recently, we have shown that SASP is dependent on expulsion of cytosolic chromatin fragments (CCF) from the nucleus into the cytoplasm of senescent cells. We have recently linked mitochondrial dysfunction to CCF production through a retrograde mitonuclear signaling pathway. This pathway is blocked by histone deacetylase inhibitors through an unknown mechanism. Unexpectedly, we recently discovered the histone deacetylase HDAC7 localizes in the nucleus of senescent cells, is required for CCF formation, and is sensitive to mitochondrial status. We hypothesize that HDAC7 is a novel component of mitochondria-nucleus retrograde signaling in senescent cells. This proposal has two Aims, to: 1) Determine the mitonuclear signaling role of HDAC7, 2) Determine the nuclear role of HDAC7 in CCF formation. Elucidation of the mechanism of this signaling pathway is of interest to all biologists but can also identify therapeutic targets for reduction of SASP. This approach can uncover alternatives to senolytic drugs for treatment of age-associated disease and promote healthy aging.

项目总结