Autoimmunity and emphysema and risk of osteoporosis in smokers

吸烟者的自身免疫和肺气肿以及骨质疏松症的风险

基本信息

批准号：
9916794
负责人：
JESSICA BON
金额：
$ 38.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9916794
关键词：
Age Alveolar Macrophages Antibodies Autoantibodies Autoimmune Process Autoimmune Responses Autoimmunity Binding Binding Proteins Biological Assay Biological Markers Bone Density Cachexia Cause of Death Cells Chronic Obstructive Airway Disease Data Dentin Diagnostic radiologic examination Disease Disease Progression Endoplasmic Reticulum Enzyme-Linked Immunosorbent Assay Female Foundations Fracture Future Goals Heat shock proteins High Prevalence Human Immune Targeting Immune response Immunoglobulin G Immunohistochemistry Immunologic Markers Immunologics Immunomodulators In Vitro Incidence Inflammation Mediators Inflammatory Investigational Therapies Link Literature Longitudinal cohort Lung diseases Measurement Measures Mediating Molecular Molecular Chaperones Morbidity - disease rate NF-kappa B Natural History Osteoclasts Osteoporosis Osteoporosis prevention Participant Pathogenesis Pathogenicity Pathologic Patient Selection Patients Physical activity Physiological Population Prevalence Prevention strategy Process Production Proteins Pulmonary Emphysema Reaction Time Reverse Transcriptase Polymerase Chain Reaction Risk Risk Factors Risk stratification Roentgen Rays Role Scanning Series Smoker Smoking Status Stains Steroids Testing United States Variant Woman X-Ray Computed Tomography airway obstruction biological adaptation to stress bone bone resorbing activity bone turnover clinically significant cohort cytokine endoplasmic reticulum stress falls follow-up glucose-regulated proteins improved insight male men mortality novel nuclear factors of activated T-cells osteoporosis with pathological fracture patient population physical inactivity precursor cell public health relevance pulmonary function response screening guidelines smoking-related lung disease targeted agent tartrate-resistant acid phosphatase time interval tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Low bone mineral density (BMD) has been linked to chronic obstructive pulmonary disease (COPD) independent of traditional osteoporosis risk factors including steroid use, cachexia, and decreased physical activity. Although the increased prevalence of osteoporosis contributes to morbidity and mortality in COPD patients, little is known regarding indications for BMD assessment or osteoporosis mechanisms in this susceptible population. The rate of BMD loss is an independent risk factor for fracture. Yet, cross-sectional dual x-ray absorptiometry (DXA) assessment of BMD provides no information about rate of BMD decline. Immunologic alterations contribute to the pathogenesis of both COPD and osteoporosis but the role of autoimmunity in COPD-related osteoporosis has not been studied. An independent association between emphysema and low BMD has been supported by the literature, but the mechanism for this association is also unknown. This project's overall goal is to study how specific autoimmune processes relate to concurrent emphysema progression and accelerated BMD decline in male and female smokers with lung disease. This goal will be accomplished through extension to six years of an already established longitudinal cohort with pre- existing baseline and two-year assessments of BMD, radiographic emphysema, pulmonary function, and autoimmune biomarker levels. The association of an autoimmune biomarker, anti-glucose regulated protein 78 (GRP78) IgG, with emphysema progression, measured by quantitative CT scan, and BMD loss, measured by serial DXA, over the six-year time interval will be studied in smokers with emphysema or airflow obstruction. A series of in vitro osteoclast studies will be performed to assess the effect of autoantibodies to GRP78, an endoplasmic reticulum (ER) chaperone protein intimately involved in the ER stress response, on osteoclast formation, proliferation, and activity. The findings from this project will identify criteria for smokers at risk of accelerated BMD loss in whom early and serial measurements of BMD may be warranted, provide insight into pathogenic mechanisms linking emphysema and osteoporosis, and provide novel targets for osteoporosis prevention and treatment strategies in patients with COPD.

描述（由申请人提供）：低骨矿物质密度（BMD）与慢性阻塞性肺病（COPD）有关，与传统的骨质疏松症危险因素（包括类固醇使用、恶病质和体力活动减少）无关，尽管骨质疏松症患病率增加会导致骨质疏松症。慢性阻塞性肺病 (COPD) 患者的发病率和死亡率，对于这一易感人群的 BMD 评估或骨质疏松机制知之甚少。 BMD 损失率是骨折的独立危险因素。 BMD 的 X 射线吸收测定法 (DXA) 评估没有提供有关 BMD 下降率的信息。免疫学改变导致 COPD 和骨质疏松症的发病机制，但尚未研究自身免疫在 COPD 相关骨质疏松症中的作用。和低 BMD 已得到文献支持，但这种关联的机制尚不清楚。该项目的总体目标是研究特定的自身免疫过程如何与并发肺气肿进展和相关。患有肺部疾病的男性和女性吸烟者的骨密度加速下降，这一目标将通过将已经建立的纵向队列延长至六年来实现，该队列具有预先存在的基线和对骨密度、放射学肺气肿、肺功能和自身免疫生物标志物的两年评估。自身免疫生物标志物抗葡萄糖调节蛋白 78 (GRP78) IgG 与肺气肿进展（通过定量 CT 扫描测量）和 BMD 损失（通过系列 DXA 测量）之间的关联。将在患有肺气肿或气流阻塞的吸烟者中进行为期六年的研究，将进行一系列体外破骨细胞研究，以评估 GRP78 自身抗体的作用，GRP78 是一种与 ER 应激反应密切相关的内质网 (ER) 伴侣蛋白。，关于破骨细胞的形成、增殖和活性。确定有 BMD 加速损失风险的吸烟者的标准，这些吸烟者可能需要进行早期和连续的 BMD 测量，深入了解肺气肿和骨质疏松症之间的致病机制，并为 COPD 患者的骨质疏松症预防和治疗策略提供新的目标。