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Exploring Determinants of Intrinsic DNA Load Towards Inflammaging

探索导致炎症的内在 DNA 负荷的决定因素

基本信息

批准号：
10373598
负责人：
Yuk Yuen Lan
金额：
$ 24.66万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10373598
关键词：
Abate Aging Algorithms Ataxia Ataxia Telangiectasia Autoimmune Autoimmunity Automobile Driving Autophagocytosis Biological Biological Assay Biological Process Biology Cell Aging Cell Nucleus Cells Cellular Morphology Chromatin Chronic Clustered Regularly Interspaced Short Palindromic Repeats Cyclic GMP Cytosol DNA DNA Damage DNA Virus Infections Diabetes Mellitus Disease Exhibits Family Foundations Future Genomic Instability Heart Diseases Homeostasis Human Immune Immune response Immunity Immunofluorescence Immunologic Impaired cognition Infection Inflammaging Inflammation Inflammatory Interferon Type I Interferons Intrinsic factor Knock-out Knockout Mice Ligands Malignant Neoplasms Mediating Mitochondrial DNA Modeling Mus Nuclear Optics Pathologic Pathology Pathway interactions Patients Pattern Phenotype Play Ploidies Polyarthritides Premature aging syndrome Production Progeria Property Retrotransposon Risk Role Signal Transduction Sterility Stimulator of Interferon Genes System Tissues base cell growth clinically relevant ds-DNA endonuclease extranuclear DNA immune activation immunogenic improved insight member novel novel strategies novel therapeutic intervention nuclease overexpression response senescence sensor systemic inflammatory response theories transcriptomics

项目摘要

PROJECT SUMMARY Sterile inflammation is exhibited in aging‐related conditions, including heart disease, cancer, diabetes, and cognitive decline. Such hyperinflammation typically displays an altered immune response comprising a type I interferon response and downstream senescence-associated secretory phenotype (SASP). The intrinsic factors that induce this chronic low-grade inflammation are not well understood. In studying the initiation of autoimmune polyarthritis in mice lacking the lysosomal endonuclease Dnase2a, we discovered a cell‐autonomous pathway through which damaged nuclear DNA is trafficked to the cytosol where it is recognized by the innate cytosolic DNA sensing cGAS-STING axis, triggering an inflammatory cascade. In healthy cells, nuclear DNA found in the cytosol is removed via autophagy for lysosomal degradation by DNASE2A, which degrades double-stranded DNA (dsDNA)—ligand for the DNA sensor cGAS. Consistent with this notion that damaged or irreparable nuclear DNA is a trigger of immunity when mis- localized and accumulated in the cytosol, elevated loads of extranuclear DNA in replicative senescent cells and cells from ataxia (AT) and progeria (HGPS) patients engage the same DNA sensing pathway leading to persistent inflammation. Controlling the intrinsic DNA load is thus critical to avoid sterile inflammation. While nucleases can clear DNA, unknown DNA export factors may facilitate DNA exit to the cytosol. By targeting curated sets of potential nucleases and DNA export factors, we propose to identify unknown intrinsic DNA controlling factors in a single-cell based CRISPR knockout optical screen by assaying dsDNA content using immunofluorescence. Hits will be validated for their DNA export or degradative function and ranked for their involvement in senescence and STING activation downstream of cGAS. Selected tops hits, along with DNASE2A, will be evaluated for their capacity in suppressing inflammation and SASP in senescent cells and AT and HGPS patient cells. In Dnase2a knockout mice, we will investigate immune cell phenotype in tissues to understand the mechanisms underlying the systemic senescent pathology. The identification and characterization of new determinants in inflammation and senescence will add new insights to the basic biology of DNA-mediated immunity and open up novel strategies in modulating inflammation to benefit aging-associated pathologies, including interferonopathy and laminopathy, autoimmunity and cancer.

项目总结