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Trained innate immunity and periodontitis-associated comorbidities

训练有素的先天免疫和牙周炎相关合并症

基本信息

批准号：
10551226
负责人：
Georgios Hajishengallis
金额：
$ 37.38万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10551226
关键词：
Address Affect Arthritis Bone Marrow Bone Marrow Cells Bone Marrow Transplantation Cardiovascular Diseases Cell Separation Cells Cellular Assay Chromatin Chronic Chronic Disease Data Development Disease Epidemiology Epigenetic Process Future Gene Expression Hematopoietic stem cells Immune Immunologic Memory Infection Inflammation Inflammatory Inflammatory Arthritis Interleukin-1 Receptors Interleukin-1 beta Investigation Knowledge Leukocytes Ligature Long-Term Effects Mediating Memory Modification Mus Myelogenous Myeloid Cells Myelopoiesis Natural Immunity Non-Insulin-Dependent Diabetes Mellitus Oral PTPRC gene Periodontal Diseases Periodontitis Peripheral Phenotype Pre-Clinical Model Predisposition Procedures Production Proliferating Readiness Rheumatoid Arthritis Role Seminal Signal Transduction Stimulus Study models System Systemic disease Tamoxifen Testing Training Transplantation Transposase chronic inflammatory disease collagen antibody induced arthritis comorbidity congenic cytokine design experimental study holistic approach inflammatory bone loss insight novel novel therapeutic intervention pharmacologic progenitor stem cells systemic inflammatory response therapeutic target transcriptomics transmission process

项目摘要

Project Summary Periodontal disease (PD) is a prevalent oral inflammatory condition that is epidemiologically associated with systemic disorders (comorbidities), such as, cardiovascular disease, rheumatoid arthritis, and type-2 diabetes. An independent association between PD and comorbidities remains even after adjustment for confounders. A possible factor contributing to this independent association is that PD can cause low-grade systemic inflammation, which may in turn influence comorbidities. The relationship between PD and systemic comorbidities is bidirectional in that systemic diseases can also promote susceptibility to PD. However, there is no known unifying causal mechanism that can explain how PD affects and is affected by comorbidities. To mechanistically explain the reciprocal association between PD and comorbid conditions, a novel hypothesis is proposed based on the recent concept that systemic inflammatory stimuli can cause epigenetic rewiring of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow, which enables these cells to give rise to ‘trained’ myeloid cells that can respond more strongly to future stimuli. This concept represents a form of innate immune memory and is known as ‘trained innate immunity’ (TII). TII can be protective in infections but potentially detrimental, hence maladaptive, in inflammatory disorders. Thus, given that chronic inflammatory diseases are – in large part – driven by the action of inflammatory myeloid cells, inflammation-driven transcriptomic and epigenetic alterations in their bone marrow progenitors are likely to influence the initiation or the progression of different chronic inflammatory disorders that emerge as comorbidities. This project involves investigation of the comorbidity of PD with another inflammatory bone loss disorder, rheumatoid arthritis. The overarching hypothesis is that maladaptive TII constitutes a mechanistic basis for the comorbid connection of PD and arthritis, which are studied using validated preclinical models, ligature-induced PD (LIP) and collagen antibody-induced arthritis (CAIA), respectively. The objective of Aim 1 is to show that inflammation-adapted HSPCs in the bone marrow mediates the comorbid association of PD and inflammatory arthritis. That the proposed maladaptive effect is mediated by inflammation-adapted (‘trained’) HSPCs will be tested by bone marrow transplantation experiments. Aim 2 was designed to investigate whether experimental PD induces transmissible epigenetic modifications in bone marrow progenitors towards a maladaptive inflammatory phenotype that underlies the development of inflammatory comorbidities. Further studies are proposed to show that interleukin-1β acts on HSPCs to mediate LIP-induced trained myelopoiesis and increased disease activity (Aim 3). If successful, this project will provide a unifying network for and mechanistic insights into the interconnection of inflammatory comorbidities and maladaptive TII in the bone marrow. Such conceptual framework could also provide a platform for novel therapeutic interventions targeting inflammatory comorbidities via pharmacological modulation of TII.

项目总结