Mechanogenomics of the asthmatic airway epithelium

哮喘气道上皮的机械基因组学

• 批准号: 10642317
• 负责人: Margherita De Marzio
• 金额: $ 18.82万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642317
• 关键词: Affect; Asthma; Award; Basal Cell; Binding; Biological; Biomechanics; Biometry; Biophysics; Bronchial Spasm; Bronchoconstriction; Cell Communication; Cells; Chronic; Clinical; Clinical Data; Coagulation Process; Collagen; Complex; Computational Biology; Confusion; Data; Deposition; Development; Disease; Environment; Epithelial Cells; Epithelium; Event; Extracellular Matrix; Future; Genetic; Genetic Transcription; Genomics; Goals; Goblet Cells; Grant; Heterogeneity; Human; Immune response; In Vitro; Inflammation; Inflammatory; Link; Mechanical Stress; Mechanics; Mediating; Medicine; Mentors; Modeling; Modernization; Molecular; Morphology; Muscle Contraction; Nature; Pathogenesis; Pathogenicity; Pathologic; Pathologic Processes; Pathway interactions; Patients; Pattern; Phenotype; Physics; Population Study; Positioning Attribute; Process; Proliferating; Proteins; Pulmonology; Qualifying; Research; Research Personnel; Resources; Role; Route; Science; Scientist; Signal Pathway; Stimulus; Systems Biology; Testing; Therapeutic; Tissues; Training; airway epithelium; airway goblet cell hyperplasia; airway inflammation; airway remodeling; asthmatic; asthmatic airway; bronchial epithelium; candidate identification; career; cell type; epithelial to mesenchymal transition; experience; experimental study; genome-wide; in vivo; innovation; mechanical force; mechanotransduction; migration; molecular targeted therapies; network models; novel; pressure; prevent; programs; repaired; respiratory smooth muscle; response; single-cell RNA sequencing; skills; targeted treatment; therapeutic biomarker; therapeutic candidate; therapeutic target; trait; transcriptome sequencing; translational impact; volunteer; wound healing

Summary/Abstract Airway wall remodeling is one of the most documented hallmarks of asthma. Despite being a key clinical trait of long-term asthma, this pathological condition remains largely uncontrolled even with front-line therapies. Remodeling processes have been traditionally described as an aberrant response to chronic inflammation. However, this picture is challenged by increasing evidence of airway remodeling as a primary mechanotransduction event. Recent studies point to mechanical abnormalities in the airway epithelium as a core factor of asthma pathogenesis. In vitro and in vivo experiments show that the mechanical effects of asthmatic bronchoconstriction can trigger alone genomic, molecular, and morphological patterns of airway remodeling even in the absence of inflammatory stimuli. As such, the traditional picture of asthma as a predominantly inflammatory disease is giving way to a complex, multifactorial scenario where mechanical forces, immune response, and tissue remodeling all contribute to the development of the disease. Building upon these findings, this proposal hypothesizes that the mechanogenetic response of the airway epithelium to excessive mechanical stress constitutes a route to aberrant airway remodeling that is independent of inflammation. To test this hypothesis, Dr. De Marzio will develop a novel systems biology approach that combines genomics, biostatistics, and network medicine. RNA-Sequencing and clinical data from asthma population studies will be integrated with protein interaction networks to: 1) Identify the mechanogenetic signature of bronchoconstriction in the asthmatic epithelium and understand its role on asthmatic phenotypes; 2) define the role of airway epithelial cell heterogeneity in response to mechanical compression; and 3) determine the signaling pathways mediating compression-induced airway remodeling to discover candidate therapeutic markers. In doing so, this project will represent the first comprehensive study on the mechanogenomics of asthma. The intrinsic interdisciplinary nature of this proposal makes Dr. De Marzio uniquely qualified to pursue this research direction. The proposed research will leverage her physics background and her experience in computational biology and network modeling to understand the pathogenic role of mechanical forces in asthma. For the successful development of this project, she will receive additional training in airway pathobiology and pulmonary medicine and she will be supported by an outstanding mentoring team composed of biologists, network scientists, and pulmonologists. Dr. De Marzio's long-term career goal is to establish an independent research program at the intersection of genomics, biomechanics, and network science. The resources offered by this award combined with the rich intellectual environment of the Channing Division of Network Medicine will put her in an advantageous position to transition to independence and submit multiple R01s. Dr. De Marzio's findings will pave the way for the future development of a mechanomedicine of asthma.

摘要/摘要 气道壁重塑是哮喘最常见的症状之一。尽管这是该病的一个关键临床特征 长期哮喘，即使采用一线治疗，这种病理状态在很大程度上仍未得到控制。 重塑过程传统上被描述为对慢性炎症的异常反应。 然而，越来越多的证据表明，呼吸道重塑是一种主要疾病，这一图景受到了挑战。 机械转导事件。最近的研究指出，以呼吸道上皮为核心的机械异常 哮喘发病因素。体外和体内实验表明，哮喘的机械效应 支气管收缩甚至可以单独引发基因组、分子和形态上的气道重塑。 在没有炎性刺激的情况下。因此，传统上认为哮喘是一种主要的炎症性疾病 疾病正在让位于一种复杂的、多因素的场景，机械力、免疫反应和 组织重塑都有助于疾病的发展。在这些发现的基础上，本提案 假设呼吸道上皮对过度机械应力的机械发生反应 构成了一条独立于炎症的异常呼吸道重塑的途径。为了测试这一点 假设，德·马尔齐奥博士将开发一种新的系统生物学方法，将基因组学、生物统计学、 和网络医疗。来自哮喘人群研究的RNA测序和临床数据将与 蛋白质相互作用网络：1)确定哮喘患者支气管收缩的机械发生特征 2)明确呼吸道上皮细胞在哮喘表型中的作用 机械压缩反应的异质性；以及3)决定调节信号通路 压迫诱导的气道重塑以寻找候选治疗标记物。通过这样做，这个项目将 代表了对哮喘机制基因组学的第一个全面研究。内在的跨学科 这一建议的性质使德马尔齐奥博士成为唯一有资格追求这一研究方向的人。建议数 研究将利用她的物理背景和她在计算生物学和网络方面的经验 建模以了解机械力在哮喘中的致病作用。为了…的成功开发 在这个项目中，她将接受呼吸道病理生物学和肺部医学的额外培训，她将 由生物学家、网络科学家和肺病学家组成的杰出指导团队提供支持。 德·马尔齐奥博士的长期职业目标是在 基因组学、生物力学和网络科学。该奖项提供的资源与富人相结合 昌宁网络医学部的智力环境将使她处于有利地位 过渡到独立并提交多个R01。德·马尔齐奥博士的发现将为未来铺平道路 开发一种治疗哮喘的机械药物。