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: 10338147
• 负责人: Alberta L. Wang
• 金额: $ 19.48万
• 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 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10338147
• 关键词: 6 year old; Advisory Committees; Affect; Allergic; Allergic Disease; Applications Grants; Asthma; Biological; Biological Markers; Biological Process; Characteristics; Child; Childhood; Childhood Asthma; Clinical; Clinical Data; Computer Analysis; Data; Development; Development Plans; Disease; Disease Progression; Epidemiology; Epigenetic Process; Functional disorder; Future; GAB2 gene; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Goals; Grant; Hospitals; Household; Hypersensitivity; IgE; Immune signaling; Income; Individual; Institution; Intervention; Investigation; Knowledge; Lead; Life; Link; Longitudinal Studies; Low Birth Weight Infant; Manuscripts; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Messenger RNA; MicroRNAs; Monitor; Multiomic Data; Nasal Epithelium; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pediatric cohort; Peripheral; Persons; Positioning Attribute; Preparation; Prognostic Marker; Regulation; Research; Research Personnel; Research Proposals; Resources; 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

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. With the support of her division, mentors, and scientific advisory committee and the resources available at her institution, the candidate is ideally positioned to achieve her goal of becoming a successful independent investigator in the epidemiology and epigenetics of asthma and allergic diseases.

哮喘和鼻炎具有很强的遗传因素，是最常见的慢性呼吸道疾病 全球分别影响 3.39 亿和 5 亿人。过敏性鼻炎和非过敏性鼻炎都是 经过充分研究的哮喘发生的危险因素，与特应性和 IgE 致敏无关，并且高达 80%的哮喘患者伴有鼻炎。相反，哮喘也是发生以下疾病的危险因素： 鼻炎提示上呼吸道和下呼吸道之间存在共同的病理生理联系。个人有 哮喘和鼻炎共病更有可能出现频繁且严重的哮喘恶化。 目前，对哮喘和鼻炎的共病发展的理解存在未满足的需求， 包括哪些患者面临风险以及为什么患有共病的患者病情严重程度增加。 microRNA (miRNA) 已成为重要的预测生物标志物和发病机制的调节因子 哮喘和鼻炎。然而，miRNA-信使 RNA (mRNA) 调节网络在哮喘中的作用 合并鼻炎尚不清楚。该 K23 奖励提案的总体假设是，共病 哮喘和鼻炎的发展可以通过临床因素进行预测，并受到 miRNA-mRNA 的调节 网络。具体目标 1 将评估儿童早期共病发展的临床预测 维生素 D 产前哮喘减少试验 (VDAART) 中的疾病以及儿童、过敏、环境、 斯德哥尔摩流行病学 (BAMSE) 队列并创建经过验证的临床预后工具来识别高风险 可能受益于早期监测和干预的儿童。具体目标 2 将确定独特的 外周血中调节哮喘合并症的 miRNA-mRNA 通路和调节网络 来自 VDAART、BAMSE 和儿童哮喘管理计划 (CAMP) 队列的儿童鼻炎 识别候选 miRNA 和生物通路，可作为基于 miRNA 的未来靶点 疗法和生物标志物。具体目标 3 将前瞻性验证哮喘的 miRNA-mRNA 特征 招募的受试者的外周全血和局部鼻上皮患有共病鼻炎 布莱根妇女医院确定了患者中共有的和组织特异性的致病途径 外周血和局部初级气道组织。通过此 K23 奖项提案，候选人将 完成指导、课程、会议、以患者为中心的研究、统计和 计算分析、手稿提交和 R01 拨款准备。她将发展新知识 和临床、转化和计算研究方面的技能，并产生新的假设和数据 为未来的独立调查提供基础。在她的部门、导师和同事的支持下 凭借科学咨询委员会及其所在机构的可用资源，候选人处于理想的位置 实现成为流行病学和表观遗传学领域成功的独立研究者的目标 哮喘和过敏性疾病。