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.

哮喘和鼻炎有很强的遗传成分，是最常见的慢性呼吸道疾病 在全球范围内，分别影响3.39亿和5亿人。过敏性和非过敏性鼻炎都是 与特应性和IgE致敏无关的哮喘发展的危险因素研究得很好，最高可达 80%的哮喘患者伴有鼻炎。相反，哮喘也是发展为 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。具有以下特征的个人 同时患有哮喘和鼻炎的人更有可能经历频繁和严重的哮喘恶化。 目前，在理解哮喘和鼻炎的共同发展方面存在着未得到满足的需求， 包括哪些患者有风险，以及为什么合并疾病的患者疾病严重程度增加。 MicroRNAs(MiRNAs)已成为一种重要的预测生物标志物和肿瘤发病机制的调节因子。 哮喘和鼻炎。然而，miRNA-Messenger RNA(MRNA)调节网络在哮喘中的作用 并存的鼻炎尚不清楚。这项K23奖项提案的总体假设是，联合竞标 哮喘和鼻炎的发展可以由临床因素预测，并由miRNA-mrna调节。 网络。特异靶1将评估儿童早期临床预测合并症的发展 维生素D产前哮喘减少试验中的疾病(VDAART)和儿童，过敏，环境， 斯德哥尔摩流行病学(BAMSE)队列，并创建有效的临床预后工具来识别高危 可从早期监测和干预中受益的儿童。具体目标2将确定独特的 外周血中miRNA-mRNAm RNA通路和调控网络调控哮喘并发疾病 VDAART、BAMSE和儿童哮喘管理计划(CAMP)队列中的儿童鼻炎 确定可能成为基于miRNA的未来靶点的候选miRNAs和生物途径 治疗和生物标记物。特异靶向3将前瞻性地验证哮喘的miRNA-mRNA签名 在从中国招募的受试者中，外周全血和局部鼻上皮合并鼻炎 布里格姆和妇女医院确定共同的和组织特异性的致病途径 外周血和局部主要呼吸道组织。通过这项K23奖励计划，候选人将 完成指导、课程作业、会议、以患者为导向的研究、统计和 计算分析、手稿提交和R01拨款准备。她将发展新的知识 以及临床、转换和计算研究方面的技能，并生成新的假设和数据 为今后的独立调查奠定了基础。在她的部门、导师和 科学咨询委员会和她所在机构的可用资源，候选人处于理想的位置 为了实现她的目标，成为一名成功的流行病学和表观遗传学的独立研究者 哮喘和过敏性疾病。