Inflammasome regulation underlying sexual dimorphism in periodontitis

牙周炎性别二态性背后的炎症小体调节

• 批准号: 10639301
• 负责人: Julie Teresa Marchesan
• 金额: $ 71.92万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639301
• 关键词: Adjuvant Therapy; Adult; Alveolar Bone Loss; American; Biological; Biological Process; Bone Diseases; CASP1 gene; Caring; Cell Death; Cell membrane; Chronic Disease; Data; Data Analyses; Development; Disease; Excision; Female; Fostering; Gene Deletion; Genetic; Gingiva; Gingivitis; Goals; Health; Health Personnel; High Prevalence; Homeostasis; IL18 gene; Immune response; Individual; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Innate Immune System; Interleukin-1; Interleukin-1 beta; Interleukins; Knowledge; Ligature; Modeling; Mucous Membrane; Mus; Ovariectomy; Pathway interactions; Patients; Pattern recognition receptor; Peptide Hydrolases; Periodontal Diseases; Periodontitis; Periodontium; Population; Prevalence; Prevention; Process; Production; Quality of life; Regulation; Resolution; Role; Severities; Severity of illness; Sex Differences; Signal Transduction; Testing; Therapeutic; Tissues; Tooth Loss; Tooth structure; Woman; biological sex; bone; bone loss; bone repair; cell type; cohort; comparative efficacy; cytokine; healing; human tissue; immune cell infiltrate; innate immune function; male; men; microbial; mortality; novel; prevent; protein complex; repaired; response; sensor; sex; sexual dimorphism; standard of care; therapeutic target; tissue repair; translational applications; treatment response

ABSTRACT Periodontitis is a male-dominant, heterogeneous, inflammatory disease of the bone and tissues supporting the tooth. It is one of the most prevalent non-communicable chronic diseases, with ~50% prevalence in the American population. Currently, there are no adjuvant therapies available to treat the 20-25% of “hyper-inflammatory” patients that progress to tooth loss despite appropriate standard of care. In support of this current proposal, inflammasome modulation has been proposed to treat several inflammatory diseases. Inflammasome is required for processing of pro-interleukin (IL)-1, pro-IL-18, and Gasdermin-D into their mature, functional forms. Despite the common knowledge that IL-1 is sexually dimorphic and a marker for periodontal inflammation, its role as a direct driver of disease development in both females and males is not clear. We find that inflammasome activation has both a protective and destructive effect on periodontal tissue that is differentially regulated between the sexes. Our data suggest the existence of sex-based distinct pathways of periodontal bone loss. This study will expand our current knowledge on the role of inflammasomes in periodontal inflammation and tissue destruction in females and males. We propose to build upon our findings to develop the below aims: Aim 1: Define the impact of biological sex in inflammasome activation during periodontal disease development and progression. Aim 2: Define the relationship between inflammasomes and periodontal tissue repair. Aim 3: To use a new strategy to target inflammasomes for preventing murine periodontitis. 1

摘要 牙周炎是一种男性为主的、异质性的骨和组织炎症性疾病。 支撑着牙齿。它是最常见的非传染性慢性病之一， 美国人口中约50%的患病率。目前，还没有可用的辅助疗法。 治疗20%-25%的高炎症患者，这些患者尽管有牙齿脱落，但仍会进展为牙齿脱落 适当的护理标准。为了支持这一当前的提议，炎症小体调制已经 已被提议用于治疗几种炎症性疾病。需要炎膏才能进行加工 将前白介素1、前白介素18和胃动素-D转化为成熟的功能性形式。尽管 众所周知，IL-1是性二态的，是牙周的标志 炎症，作为女性和男性疾病发展的直接驱动因素，它的作用不是 安全。我们发现，炎性小体的激活既有保护作用，也有破坏作用 不同性别之间调节不同的牙周组织。我们的数据表明 存在以性别为基础的不同的牙周骨丢失途径。这项研究将扩大我们的 炎症小体在牙周炎和牙周组织中作用的研究现状 对女性和男性的毁灭。我们建议在我们的调查结果的基础上开发以下内容 目的：目的1：明确生物性别在牙周炎症小体激活中的作用 疾病的发展和进展。目标2：定义炎性小体之间的关系 和牙周组织修复。目标3：使用一种新的策略来针对炎症体 预防小鼠牙周炎。 1