The Phathophenotype Landscape of Complex Disease

复杂疾病的表型景观

• 批准号: 8502189
• 负责人: Joseph Loscalzo
• 金额: $ 64.18万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-18 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502189
• 关键词: Acute; Acute myocardial infarction; Alleles; Animal Model; Anti-Inflammatory Agents; Apoptosis; Aspirin; Cell model; Cells; Chronic Disease; Clinical; Communities; Complex; Computer Architectures; Data; Data Set; Development; Disease; Disease Pathway; Disorder by Site; Elements; Environment; Equilibrium; Exercise; Fibrinolytic Agents; Fibrosis; Genes; Genome; Genomics; Goals; Health; Human; Incidence; Individual; Inflammation; Inflammatory; Instruction; Intervention Trial; Ischemic Stroke; Knowledge; Laboratories; Literature; Maps; Measures; Mediator of activation protein; Medicine; Modeling; Molecular; Pathogenesis; Pathway interactions; Population; Prevention strategy; Primary Prevention; Principal Investigator; Process; Research; Sampling; Staging; Structure; System; Testing; Therapeutic; Therapeutic Effect; Thromboembolism; Thrombosis; Validation; Variant; Venous; Woman; abstracting; arm; base; body system; cohort; design; gene function; genetic analysis; genome wide association study; human disease; interdisciplinary approach; network models; novel therapeutics; population based; predictive modeling; pulmonary arterial hypertension; randomized placebo controlled trial; response; rosuvastatin

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)

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地显然显现的器官系统定义的，并且通常在末期。生物医学界现在认识到，许多不同的疾病具有常见的机制和常见的中间病态型（例如炎症，血栓形成，凋亡和纤维化）。基于这种疾病发病机理的观点，可以将疾病表达部位视为局部环境的结果以及在该环境中中等病理表型决定因素的差异表达。因此，我们提出的是一种核心假设，即不同的复杂疾病受共同网络相关的中间病理型型的共同网络决定因素的控制，而区分这些复杂疾病的原因是中间病原体的平衡，以及它们在其表达中的分子环境中的平衡。为了检验这一假设，我们将重点关注三种不同的疾病 - 急性心肌梗塞，静脉血栓栓塞和急性缺血性中风和两种中间病理表型炎症和血栓形成 - 病毒 - 三个三个跨学科的特定目标。 首先，我们将开发控制炎症和血栓形成的途径网络模型。同时，我们将利用两项基于人群的大型整个基因组扫描来执行结构化的遗传分析，以识别与不同疾病有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和彼此区分的“炎症”和“血小板”元素的子网图。其次，使用抗炎剂rosuvastatin的试验和抗血栓形成剂，阿司匹林在最初健康的个体中得出的数据集，我们将研究炎症体和血小板体对每种疾病的发生率的治疗性扰动对每种疾病的发生率的影响。我们还将利用相关的细胞系统和动物模型的相关性，迭代机制研究中常见的炎性体和血小板体的关键分子介质。第三，我们将整合炎症和血栓形成的网络模型，以开发这些疾病表现的预测性，概率，多元模型。相关性（请参阅说明）：综上所述，这些互补的跨学科方法的重点是三种常见的慢性病，​​应提供有关以机械和分子严格的方式重新定义这些疾病的信息和潜在策略。如果这种方法成功，它将为生物医学界提供重新定义许多复杂人类疾病的机会，从而导致潜在的新型治疗和预防策略，并促进真正个性化的（个性化）医学的发展。 （抽象的结尾）