Biostatistics and Systems Medicine Core Unit (Z2-Project)

最先进的生物统计学和系统医学使大多数复杂和异质疾病的研究发生了革命性的变化。因此，对单个数据集的深入生物数学分析和多维数据集的集成使得能够以公正的方式定义分子网络及其对疾病发病机制的意义，并且达到了经典生物医学研究方法无法实现的程度。虽然这些方法现在经常应用于常见疾病，如心血管疾病，并已成为推动患者护理向精准医学水平发展的驱动力，但它们在包括类天疱疮(PD)在内的不常见疾病中的应用仍处于初级阶段。然而，特别是在这些自然样本量较低的疾病中，利用、外推和整合关于单个患者的所有可用数据集的复杂生物数学/系统医学方法是以经济高效的方式进一步阐明这些疾病的关键。为了开发PD的这些新的可能性，并确保对CRU产生的所有数据集进行最全面的分析和科学利用，在第一个FP中设立了核心单位生物统计和系统医学(Z2项目)。在第二个FP中，Z2-Project将继续提供这些服务。其中，它将对PD患者进行基础性和机械性的流行病学研究，并对PD患者进行深入的表型分析，以确定患者亚组，从而揭示PDS的发病机制，并为开发个性化治疗方案做出贡献。它还将识别调控PD的基因变异和分子途径。此外，它将，例如，解决核和线粒体基因组与皮肤微生物区系之间的相互作用及其对帕金森病的影响。它还将进行一项跨基因组关联研究(TRANS)，将CRU中产生的多个组学层上的数据集相互整合，并与BP患者的表现组进行整合，以建立途径和疾病活动之间的因果关系。这将有助于确定最有希望的治疗靶点，并为PD开发新的多变量生物标记物。两者的重要性将随后在CRU项目中进行实验/临床研究。相反，Z2项目还将把临床前模型的实验结果整合到模型中，以确定小鼠和人类帕金森病的常见子网及其致病作用。因此，总而言之，Z2项目将成为CRU的大脑。这对于将CRU的结果转化为人类情况以及在最终模型系统患者中阐明帕金森病的发病机制将是至关重要的。这将是最终实现其总体目标的关键，即建立一个协调PDS效应阶段的分子过程的综合模型，以及开发选择性干扰这些过程的治疗干预措施。

State-of-the-art biostatistics and systems medicine has revolutionized the research on most complex and heterogeneous diseases. Thus, the in-depth biomathematical analysis of individual datasets and the integration of multi-dimensional datasets has enabled defining molecular networks and their significance for the pathogenesis of disease in an unbiased manner and to a degree not achievable by classical biomedical research approaches. While these approaches are now frequently applied on common diseases, such as cardiovascular disorders, and have become the driver to evolve patient care towards the precision medicine level, their application in less common diseases, including pemphigoid diseases (PDs), is still in its infancy. However, especially in these diseases with a naturally low sample size, sophisticated biomathematical/systems medicine approaches exploiting, extrapolating, and integrating all datasets available on individual patients are key to further illuminate these diseases in a cost-effective manner. To exploit these new possibilities for PDs and to ensure the most comprehensive analysis and scientific exploitation of all datasets generated in the CRU, the core unit Biostatistics & Systems Medicine (Z2-Project) was established in the 1st FP. In the 2nd FP, the Z2-Project will continue these services. Among others, it will conduct basic and mechanistic epidemiological studies and deep phenotyping of PD patients to define patient subgroups, thus uncovering the pathogenesis of PDs and contributing to the development of personalized treatment regimens. It will also identify gene variants and molecular pathways regulating PDs. In addition, it will, e.g., resolve the interactions between both the nuclear and mitochondrial genomes with the skin microbiota and their impact on PD. It will also perform a trans-ome-wide association study (transOWAS) integrating the datasets on multiple omics layers generated in the CRU with each other and with the phenomes of BP patients to establish cause-effect relationships between pathway and disease activity. This will be instrumental to identify the most promising therapeutic targets and to develop new multi-variate biomarkers for PDs. The significance of both will be subsequently experimentally/clinically addressed in the CRU projects. Conversely, the Z2-Project will also integrate experimental results from preclinical models into models to identify common subnets of PD in mice and men and their pathogenic role. Thus, collectively, the Z2-Project will be the brain of the CRU. It will be pivotal for the translation of the results of the CRU into the human situation and to elucidate the pathogenesis of PD in the ultimate model system, the patient. It will be key to finally achieve its overall aim, the establishment of a comprehensive model of the molecular processes orchestrating the effector phase of PDs, and the development of therapeutic interventions selectively interfering with these processes.