Revealing the role of blood microbiome in childhood asthma

项目总结/摘要 哮喘是全球最常见的慢性呼吸道疾病之一。肠道微生物生态失调 和肺越来越多地与哮喘的发病率和严重程度相关，这表明 是哮喘发病机制的决定性因素。然而，作为最有可能的联系 在肠道和肺之间，血液微生物组在“肠-肺轴”中的作用仍然不清楚 由于缺乏成本效益高和高通量测序方法，导致其致病性降低。事实上， 传统测序方法处理微生物DNA是不可能的，或者昂贵得令人望而却步 痕量、严重降解或由宿主DNA主导的样品，例如，在人血里我们 假设血液中微生物的存在与哮喘发生的风险有关， 并且这些微生物血液生物标志物可以通过简化的宏基因组测序方法捕获， 在深度学习框架的帮助下诊断甚至早期检测哮喘。在本申请中， 将开发用于简化宏基因组测序的应变解析计算管道， “维生素D治疗哮喘减少试验”中的血液微生物组-一项正在进行的随机、双 对881名孕妇进行了一项盲法、安慰剂对照临床试验， 和孩子的血样同时，将开发一个深度学习框架，以优化 使用血液微生物组数据的哮喘诊断和预测模型的准确性。最后，借助 新的计算管道和深度学习框架，血液微生物组在肠道中的作用， 肺轴与哮喘发病机制的关系。孙博士的分子生物学训练， 生物信息学和宏基因组学使他为这项拟议的研究做好了充分的准备。然而，在这方面， 通过分析血液微生物组数据来了解哮喘的分子基础是一个 具有挑战性的任务，需要在特定领域进一步培训。孙博士将利用优秀的知识分子 哈佛医学院及其教学医院布里格姆妇女医院的环境 （BWH）。他将有机会在BWH和HMS获得广泛的计算资源。通过正规 课程和研讨会，并与一个强大的辅导团队和世界一流的咨询帮助 与互补的专业知识委员会，孙博士将沉浸在一个培训计划，重点是 高级编程、统计建模、深度学习、呼吸病理生理学和临床 翻译.孙博士将定期或有需要时与两位导师及顾问委员会成员会面， 根据他的进展，并得到及时的反馈和建议。总的来说，孙博士的训练和研究 该计划将使他能够扩大他目前的技能，包括解决低收入国家挑战的能力。 血液样本中的微生物生物量测序，微生物组研究中的深度学习以及确定 血液微生物在哮喘发病机制中的作用，最终有助于肺部疾病的精准医疗。

Project Summary/Abstract Asthma is one of the most common chronic respiratory diseases worldwide. Microbial dysbiosis in the gut and lungs has increasingly been associated with the incidence and severity of asthma, indicating the potential of the microbiome to be a determinant factor in asthma pathogenesis. However, as the most likely connection between the gut and lungs, the role of the blood microbiome in the “gut–lung axis” is still unclear for asthma pathogenesis due to the lack of cost-effective and high-throughput sequencing methods. Indeed, it is either impossible, or prohibitively expensive, for conventional sequencing methods to handle microbial DNA samples that are in trace amounts, heavily degraded, or dominated by host DNA, e.g., in human blood. We hypothesize that the presence of microorganisms in the blood is related to the risk of asthma occurrence, and these microbial blood biomarkers can be captured by a reduced metagenomic sequencing method for diagnosis or even early detection of asthma with the help of a deep learning framework. In this application, a strain-resolved computational pipeline for the reduced metagenomic sequencing will be developed to profile the blood microbiome in the “Vitamin D Antenatal Asthma Reduction Trial” --- an ongoing randomized, double- blind, placebo-controlled clinical trial of 881 pregnant women with both questionnaires and maternal, cord, and child blood samples available. Meanwhile, a deep-learning framework will be developed to optimize the accuracy of diagnosis and prediction models for asthma using blood microbiome data. Finally, with the aid of the new computational pipeline and deep-learning framework, the role of the blood microbiome in the gut– lung axis and asthma pathogenesis will be investigated. Dr. Sun’s trainings in molecular biology, bioinformatics and metagenomics have prepared him well for this proposed research. However, understanding the molecular basis connecting asthma through the analysis of blood microbiome data is a challenging task that requires further training in specific areas. Dr. Sun will leverage the excellent intellectual environment of Harvard Medical School (HMS) and its teaching hospital Brigham and Women’s Hospital (BWH). He will have access to extensive computational resources at BWH and HMS. Through formal coursework and workshops, and with the help of a strong mentoring team and a world-class advisory committee with complementary expertise, Dr. Sun will immerse himself in a training program focusing on advanced programming, statistical modeling, deep learning, respiratory pathophysiology, and clinical translation. Dr. Sun will meet with his two mentors and advisory committee members on a regular or needed basis to present his progress and get prompt feedback and advice. Altogether, Dr. Sun’s training and research plan will enable him to expand his current skill set to include the ability to address the challenges of low microbial biomass sequencing in blood sample, deep learning in microbiome study and identifying the role of blood microbes in asthma pathogenesis, and ultimately contribute to the precision medicine of lung diseases.