Systems medicine of pulmonary arterial hypertension- SYMPAThIE study -

肺动脉高压(PAH)是一种致命性慢性肺部疾病。所有批准的多环芳烃药物只会延缓疾病的进展；因此，正在寻求新的治疗方法。在DFG提案“肺动脉高压的系统医学”的框架内，共鸣研究、创新技术“单细胞RNA测序”和“空间转录”将被用来寻找新的治疗方法。“单细胞RNA测序”能够分析成千上万个细胞中的mRNAs(“信使核糖核酸”--携带有关蛋白质结构的遗传信息的信使分子)。“空间转录学”允许研究组织中的mRNAs，即具有空间分辨率。总而言之，这些技术提供了对(患病的)细胞的先前未经授权的洞察，细胞是人类最小的生活单位。在耶鲁大学博士后期间，我创建了人类肺内皮细胞图谱，以及肺纤维化细胞图谱(包括第一次描述异常的基底细胞)。前述内皮细胞图谱将被用作生成PAH细胞图谱的参考，即数十万个单个细胞的基因表达图谱。这将使识别异常细胞群体及其在PAH肺中的病理基因表达谱成为可能。此后，PAH特有的组织病理学异常--丛状病变--以及PAH中的病理改变的肺动脉壁将被用“空间转录学”破译。在这项工作的基础上，基因调控网络和新的分子PAH治疗靶点将被开发出来，使病理细胞间的通讯正常化。汉诺威医学院拥有德国最大的肺移植中心，具备实施这一具有挑战性的项目的必要先决条件。PAH细胞图谱以及空间分辨的PAH基因表达谱将提供宝贵的科学资源，可能导致新的、迫切需要的治疗方法。

Pulmonary arterial hypertension (PAH) is a fatal chronic lung disease. All approved PAH drugs only delay the progression of the disease; accordingly, new therapeutic approaches are being sought. Within the framework of the DFG proposal "Systems Medicine of Pulmonary Arterial Hypertension", the SYMPAThIE study, the innovative technologies "Single Cell RNA Sequencing" and "Spatial Transcriptomics" will be used to find novel therapeutic approaches. "Single Cell RNA Sequencing" enables the analysis of mRNAs ("messenger ribonucleic acid" - messenger molecules that carry the genetic information about the structure of proteins) in hundreds of thousands of individual cells. "Spatial transcriptomics" allows the study of mRNAs in tissue, i.e., with spatial resolution. Together, these technologies offer previously unauthorized insights into (diseased) cells, the smallest living units in humans. During my PostDoc at Yale University, I created the human lung endothelial cell atlas, as well as the pulmonary fibrosis cell atlas (including first description of aberrant basaloid cells). The aforementioned endothelial cell atlas will be used as a reference to generate a PAH cell atlas, i.e. gene expression profiles of hundreds of thousands of individual cells. This will then allow identification of aberrant cell populations and their pathological gene expression profiles in PAH lung. Hereafter, the characteristic histopathological abnormality of PAH - the plexiform lesions - and the pathologically altered pulmonary arterial wall in PAH will be deciphered using "Spatial Transcriptomics". Based on this work, gene regulatory networks and novel molecular PAH therapeutic targets will be developed that normalize pathological intercellular communication. The necessary prerequisites for carrying out this challenging project are available at the Hannover Medical School with Germany's largest lung transplant center. The PAH cell atlas, as well as the spatially resolved PAH gene expression profiles, will provide valuable scientific resources that will potentially lead to novel, urgently needed therapeutic approaches.