Clinical prediction and epigenetic regulation of asthma and rhinitis

哮喘和鼻炎的临床预测和表观遗传调控

• 批准号: 10555544
• 负责人: Alberta L. Wang
• 金额: $ 5.4万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-10 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10555544
• 关键词: 6 year old; Administrative Supplement; Affect; Allergic; Allergic Disease; Applications Grants; Asthma; Bioinformatics; Biological; Biological Markers; Biological Process; Characteristics; Child; Childhood; Childhood Asthma; Clinical; Clinical Data; Clinical Research; Computer Analysis; Data; Development; Development Plans; Disease; Disease Progression; Epidemiology; Epigenetic Process; Event; Functional disorder; Funding; Future; GAB2 gene; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Goals; Grant; Hospitals; Household; Hypersensitivity; IgE; Immune signaling; Income; Individual; Intervention; Investigation; Knowledge; Lead; Life; Link; Longitudinal Studies; Low Birth Weight Infant; Manuscripts; Mentored Patient-Oriented Research Career Development Award; Mentorship; Messenger RNA; MicroRNAs; Monitor; Multiomic Data; Nasal Epithelium; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pediatric cohort; Peripheral; Persons; Preparation; Productivity; Prognostic Marker; Regulation; Research; Research Personnel; Research Proposals; Respiratory Disease; Rhinitis; Risk; Risk Factors; Role; Scientist; Serum; Severity of illness; Statistical Data Interpretation; Supervision; Symptoms; T-Cell Development; TCF7L2 gene; Testing; Therapeutic Intervention; Tissues; Vitamin D; Whole Blood; Woman; Work; antenatal; asthma exacerbation; asthma model; asthmatic; atopy; base; career; career development; chronic respiratory disease; circulating microRNA; clinical phenotype; clinical predictors; clinical prognostic; clinical risk; cohort; comorbidity; differential expression; early childhood; epigenetic regulation; experience; high risk; improved; insight; machine learning classification; new therapeutic target; patient oriented research; peripheral blood; predictive marker; predictive modeling; preventive intervention; prognostic tool; programs; prospective; recruit; research and development; skills; symposium; therapeutic miRNA; transcriptome; unsupervised learning

PROJECT SUMMARY/ABSTRACT Asthma and rhinitis share a strong genetic component and are the most common chronic respiratory diseases worldwide affecting 339 million and 500 million people, respectively. Both allergic and non-allergic rhinitis are well-studied risk factors for the development of asthma, independent of atopy and IgE sensitization, and up to 80% of asthmatics have concomitant rhinitis. Conversely, asthma is also a risk factor for the development of rhinitis suggesting a common pathophysiological link between the upper and lower airways. Individuals with comorbid asthma and rhinitis are more likely to experience frequent and severe asthma exacerbations. Currently, an unmet need exists in the understanding of the comorbid development of asthma and rhinitis, including which patients are at risk and why patients with comorbid disease have increased disease severity. microRNAs (miRNAs) have emerged as important predictive biomarkers and regulators of the pathogenesis of asthma and rhinitis. However, the role of miRNA-messenger RNA (mRNA) regulatory networks in asthma with comorbid rhinitis is not known. The overall hypothesis of this K23 award proposal is that the comorbid development of asthma and rhinitis can be predicted by clinical factors and is regulated by miRNA-mRNA networks. Specific Aim 1 will evaluate the early childhood clinical prediction of the development of comorbid disease in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) and Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) cohorts and create a validated clinical prognostic tool to identify high-risk children who may benefit from early monitoring and interventions. Specific Aim 2 will identify the unique miRNA-mRNA pathways and regulatory networks in the peripheral blood that regulate asthma with comorbid rhinitis in children from the VDAART, BAMSE, and Childhood Asthma Management Program (CAMP) cohorts to identify candidate miRNAs and biological pathways that may serve as future targets of miRNA-based therapies and biomarkers. Specific Aim 3 will prospectively validate the miRNA-mRNA signature of asthma with comorbid rhinitis across the peripheral whole blood and local nasal epithelium in subjects recruited from Brigham and Women’s Hospital to identify the shared and tissue-specific pathogenic pathways in the peripheral blood and local primary airway tissue. Through this K23 award proposal, the candidate will complete an integrated plan of mentorship, coursework, conferences, patient-oriented research, statistical and computational analyses, manuscript submissions, and R01 grant preparation. She will develop new knowledge and skills in clinical, translational, and computational research and generate new hypotheses and data that will provide the basis for future independent lines of investigation. Funding from this administrative supplement will support a bioinformatics programmer and clinical research coordinator to help accelerate the candidate’s return to productivity after a critical life event and enable her to substantially progress toward her goal of becoming a successful independent investigator in the epidemiology and epigenetics of asthma and allergic diseases.

项目摘要/摘要 哮喘和鼻炎具有很强的遗传成分，是最常见的慢性呼吸道疾病 全球影响3.39亿和5亿人。过敏和非过敏性鼻炎都是 研究哮喘，独立于应对和IgE敏感性的经过充分研究的风险因素，直到 80％的哮喘患者伴有鼻炎。相反，哮喘也是发展的危险因素 鼻炎表明上和下气道之间存在常见的病理生理联系。有个人 合并症哮喘和鼻炎更有可能经常出现严重的哮喘病情。 目前，在理解哮喘和鼻炎的合并发展中存在未满足的需求， 包括哪些患者处于危险之中，以及为什么合并症患者疾病严重程度增加。 MicroRNA（miRNA）已成为重要的预测生物标志物和调节剂 哮喘和鼻炎。然而，miRNA-Messenger RNA（mRNA）调节网络在哮喘中的作用 合并症鼻炎尚不清楚。该K23奖励提案的总体假设是合并症 哮喘和鼻炎的发展可以通过临床因素预测，并由miRNA-MRNA调节 网络。具体目标1将评估合并症发展的幼儿临床预测 维生素D产前哮喘降低试验（VDAART）和儿童，Milieu，Milieu的疾病 斯德哥尔摩，流行病学（BAMSE）队列，并创建经过验证的临床探测工具，以识别高风险 可能会从早期监测和干预措施中受益的孩子。特定目标2将确定独特 miRNA-mRNA途径和周围血液中调节哮喘的调节网络 VDAART，BAMSE和童年哮喘管理计划（CAMP）的儿童鼻炎 确定可能用作基于miRNA的未来靶标的候选miRNA和生物学途径 疗法和生物标志物。特定的目标3可能会验证哮喘的miRNA-mRNA特征 在周围全血和局部鼻上皮的合并症中，从中招募的受试者 Brigham和妇女医院确定在 外周血和局部原发气道组织。通过这项K23奖励提案，候选人将完成 综合计划，课程工作，会议，面向患者的研究，统计和 计算分析，手稿提交和R01赠款准备。她将发展新知识 以及临床，转化和计算研究的技能，并产生新的假设和数据 为将来的独立投资线提供基础。此行政补充的资金将 支持生物信息学程序员和临床研究协调员，以帮助加速候选人的回报 重大生活事件发生后的生产力，使她能够实质性地朝着成为一个目标的目标发展 成功的独立研究者在哮喘和过敏性疾病的流行病学和表观遗传学方面。