Determining the Role of Creatine Kinase in Asthma

确定肌酸激酶在哮喘中的作用

基本信息

批准号：
10744999
负责人：
Julie Gunnells Ledford
金额：
$ 23.03万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-22 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10744999
关键词：
Accounting Address Adult Affect Age Area Asthma Biological Assay Blood Buffers Cells Child Childhood Childhood Asthma Chronic Chronic Obstructive Pulmonary Disease Chronic lung disease Circulation Clinical Markers Cohort Studies Creatine Creatine Kinase Data Development Diagnosis Dose Down-Regulation Elements Environment Enzymes Epithelial Cells Future Gene Expression Heart Homeostasis House Dust Mite Allergens Human Impairment Inflammation Interleukin-13 Interleukin-6 Isoenzymes Lead Life Link Lung Mitochondria Morbidity - disease rate Mucins Mucous body substance Mus Muscle Myocardial Infarction Nasal Epithelium Nature Peptide Hydrolases Persons Phase Phenotype Phosphocreatine Play Population Predisposition Protein Isoforms Puberty Publishing Pyroglyphidae Reaction Regulation Reporting Research Resolution Respiratory System Rhabdomyolysis Role Serum Severities Signal Transduction Stat3 Signaling Pathway Symptoms Time Tissues United States Whole Blood airway epithelium airway hyperresponsiveness allergic airway disease asthma model asthmatic cohort cytokine early detection biomarkers experimental study human data inhibitor interest long-term sequelae mortality mouse model mucus clearance pharmacologic potential biomarker predictive modeling prevent protective factors pulmonary function resilience risk stratification translational study

项目摘要

Asthma is more common in children than adults, with approximately 6.2 million children under age 18 diagnosed with asthma in the US alone. Persistence of childhood asthma has been now conclusively linked to chronic lung function deficits that track into adult life. Understanding the natural course of childhood asthma and preventing its persistence into adult life are tasks of paramount importance. While a significant proportion of children with asthma overcome symptoms after the onset of puberty, the factors that confer this resilience to persistent asthma remain largely unknown. At present, there are neither established prediction models nor available biomarkers for early risk stratification of long-term sequelae of childhood asthma. Recently, in a multi-cohort study we reported for the first time that serum levels and whole blood gene expression of creatine kinase (CK) are decreased in childhood asthma. CK is an enzyme that – by catalyzing the reversible reaction of creatine and ATP to phosphocreatine and ADP – plays a vital role in cellular energy homeostasis and buffering. Further, we conducted experimental studies in a mouse model of allergic airway disease induced by the common allergen, house dust mite (HDM) in the presence and absence of a pharmacological inhibitor of CK-B. We discovered that CK-B expression significantly decreased 24 hrs after HDM challenge, yet recovered by 5 days post challenge, suggesting its importance during the resolution phase. Most notably, we found that HDM challenged mice in which CK-B was inhibited displayed a prolonged period of airway hyperresponsiveness and had a major impact on the presence of mucin in the airways. While these studies indicate for the first time a potential protective role of CK in childhood asthma, multiple elements of this association remain to be elucidated. This proposal addresses our overall hypothesis that factors in the asthmatic lung milieu lead to the down-regulation of CK isoforms, which in turn results in prolonged and worse asthma phenotypes. We will investigate 3 areas of interest regarding the CK isoforms and asthma that will lead us down the path of further mechanistic understanding: 1) expression of CK in specific respiratory epithelial cell populations and the impact on CK levels in circulation and in the lung during asthma, 2) the impact of specific factors in an asthmatic lung environment that may regulate CK expression and 3) if chronically low CK in early life impacts the severity of adult-onset asthma in mice.

哮喘在儿童中比成人更常见，大约有 620 万 18 岁以下儿童仅在美国就被诊断出患有哮喘儿童哮喘的持续存在现已明确与此相关。了解儿童哮喘的自然病程。并防止其持续进入成年生活是最重要的任务，而其中很大一部分是重要的。的哮喘儿童在青春期开始后克服了症状，这些因素赋予了他们这种适应能力目前，对于持续性哮喘仍然知之甚少，既没有建立的预测模型，也没有建立的预测模型。用于儿童哮喘长期后遗症早期风险分层的可用生物标志物。最近，在一项多队列研究中，我们首次报告了血清水平和全血基因儿童哮喘中肌酸激酶 (CK) 的表达降低 CK 是一种酶，通过催化。肌酸和 ATP 生成磷酸肌酸和 ADP 的可逆反应 – 在细胞能量中起着至关重要的作用此外，我们在过敏性气道小鼠模型中进行了实验研究。在存在或不存在某种物质的情况下，由常见过敏原屋尘螨 (HDM) 引起的疾病 CK-B 的药理学抑制剂我们发现 24 小时后 CK-B 表达显着下降。 HDM 挑战，但在挑战后 5 天恢复，表明其在解决过程中的重要性最值得注意的是，我们发现 CK-B 受到抑制的 HDM 攻击小鼠表现出延长的时间。气道高反应期并对气道中粘蛋白的存在产生重大影响。虽然这些研究首次表明 CK 对儿童哮喘具有潜在的保护作用，但多个该关联的要素仍有待阐明。该提案解决了我们的总体假设：哮喘肺环境中的因素导致 CK 亚型下调，进而导致我们将研究有关 CK 亚型的 3 个感兴趣的领域。和哮喘，这将引导我们走上进一步理解机制的道路：1) CK 的表达特定的呼吸道上皮细胞群以及对循环和肺中 CK 水平的影响哮喘，2) 哮喘肺环境中可能调节 CK 表达的特定因素的影响 3) 生命早期长期的低 CK 是否会影响小鼠成年期哮喘的严重程度。