The Phathophenotype Landscape of Complex Disease

描述（由申请人提供）：自19世纪以来，人类疾病在很大程度上是由它们最明显表现的器官系统来定义的，而且通常是在终末期。生物医学界现在认识到，许多不同的疾病具有共同的机制和共同的中间病理表型（如炎症、血栓形成、细胞凋亡和纤维化）。基于这种疾病发病机制的观点，疾病表达的部位可能被视为局部环境和该环境中中间病理表型决定因素差异表达的结果。因此，我们提出了一个中心假设，即不同的复杂疾病是由共同的中间病理表型的共同网络相关决定因素控制的，而区分这些复杂疾病的是中间病理表型之间的平衡，以及它们表达的分子环境。为了验证这一假设，我们将通过三个跨学科的具体目标，关注三种不同的疾病——急性心肌梗死、静脉血栓栓塞和急性缺血性中风——以及两种中间病理表型——炎症和血栓形成。首先，我们将开发控制炎症和血栓形成通路的网络模型。同时，我们将利用两个基于人群的全基因组扫描来进行结构化遗传分析，以确定与不同疾病相关的炎症和血栓形成途径的组成部分。通过将这种遗传分析与网络模型相结合，我们将开始构建这些疾病共有的“炎症小体”和“血栓小体”元素的子网络图，以及区分它们彼此的元素。其次，使用从抗炎剂瑞舒伐他汀和抗血栓剂阿司匹林的试验中获得的数据集，在最初的健康个体中，我们将检查炎症小体和血栓小体的治疗扰动对由基因状态决定的每种疾病发病率的影响。我们还将利用这三种疾病共同和独特的炎症小体和血栓小体的关键分子介质，利用相关的细胞系统和动物模型进行相关的、反复的机制研究。第三，我们将整合炎症和血栓的网络模型，建立这些疾病表现的预测性、概率性、多变量模型。相关性（见说明）：总的来说，这些互补的跨学科方法侧重于三种常见的慢性疾病，应该提供有关信息和潜在的策略，以机械和分子严格的方式重新定义这些疾病。如果这种方法成功，它将使生物医学界有机会重新定义许多复杂的人类疾病，导致潜在的新的治疗和预防策略，并促进真正个性化（个体化）医学的发展。（摘要结束）

DESCRIPTION (provided by applicant): Since the 19th century, human diseases have largely been defined by the organ system in which they are most obviously manifest, and often so at end-stage. The biomedical community now recognizes that many different diseases have common mechanisms and common intermediate pathophenotypes (e.g., inflammation, thrombosis, apoptosis, and fibrosis). Based on this perspective of disease pathogenesis, the site of disease expression may be viewed a consequence of the local environment and of the differential expression of determinants of the intermediate pathophenotype in that environment. We, therefore, propose as a central hypothesis that different complex diseases are governed by common network- associated determinants of common intermediate pathophenotypes, and that what differentiates these complex diseases from one another is the balance among the intermediate pathophenotypes, and the molecular context within which they are expressed. To test this hypothesis, we will focus on three different diseases-acute myocardial infarction, venous thromboembolism, and acute ischemic stroke-and two intermediate pathophenotypes-inflammation and thrombosis-via three interdisciplinary specific aims. First, we will develop network models of pathways that govern inflammation and thrombosis. Concomitantly, we will utilize two large population-based whole genome scans to perform structured genetic analysis to identify components of inflammatory and thrombotic pathways related to the different diseases. By combining this genetic analysis with network models, we will begin to construct subnetwork maps of elements of the 'inflammasome' and 'thrombosome' common to these diseases and elements that distinguish them from one another. Second, using data sets derived from trials of the anti-inflammatory agent, rosuvastatin, and the antithrombotic agent, aspirin, in initially healthy individuals, we will examine the effect of therapeutic perturbation of the inflammasome and thrombosome on the incidence of each disease as determined by gene status. We will also utilize key molecular mediators of the inflammasome and thrombosome common to and distinctive for these three diseases in correlative, iterative mechanism studies using relevant cell systems and animal models. Third, we will integrate the network models of inflammation and thrombosis to develop predictive, probabilistic, multivariate models of manifestations of these diseases. RELEVANCE (See instructions): Taken together, these complementary interdisciplinary approaches focused on three common chronic illnesses should provide information about and potential strategies for redefining these diseases in a mechanistically and molecularly rigorous way. If this approach is successful, it will afford the biomedical community the opportunity to redefine many complex human diseases, leading to potentially novel therapeutic and preventive strategies, and promoting the development of truly personalized (individualized) medicine. (End of Abstract)