NON-INVASIVE APPROACHES TO ASSESSING INFLAMMATION

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。描述(申请人提供)：尽管在更好地了解慢性炎症性疾病的免疫调节机制和遗传易感性方面取得了重大进展，包括免疫介导性关节炎、糖尿病、炎症性肠病、系统性红斑狼疮(SLE)、肾小球肾炎、血管炎、动脉粥样硬化和哮喘，但诊断和临床管理的一个主要障碍是无法轻松确定和量化累及内脏的疾病的活动性和程度。此外，目前的技术无法识别亚临床炎症，这种炎症预测高危个体在诱导缓解或一系列疾病后症状迅速复发。组织学诊断和对肠、肺、肝、肾、关节、血管、甲状腺和脑部疾病活动性的评估需要侵入性的内窥镜、经皮甚至开放手术活检，这会带来相当大的不适感和风险。我们的目标是通过将血管内皮细胞/效应器炎症细胞相互作用、天然和获得性免疫细胞激活、血管通透性和新生血管的基本知识应用于新的成像技术，开发非侵入性方法来确定几种炎症性疾病患者不可触及的器官中炎症的位置和强度。我们的研究将集中在克罗恩病、溃疡性结肠炎、系统性红斑狼疮、抗中性粒细胞胞浆抗体(ANCA)介导的血管炎和动脉粥样硬化，因为我们研究所存在包括这些疾病的基本机制、动物模型和临床调查的跨学科研究计划，每种疾病都是多器官疾病，这些疾病分别是T淋巴细胞、抗体/补体、中性粒细胞和巨噬细胞介导的疾病的原型。因此，这些重点研究的结果将适用于前面提到的所有炎症情况。将实现这一目标的具体目标如下：1.建立一个行政结构，规划和协调各项活动，促进多学科调查员小组之间的有效互动和沟通。2.组织以专题为导向的讲习班，促进当地研究人员和外部专家之间的互动，以确定确定各种器官和疾病过程中炎症的程度和活动性的最佳分子目标、检测技术和临床应用。3.支持初步研究，以确定分子靶点(第一年)，优化成像和分子/生化/免疫学技术(第一年和第二年)，在不同器官炎症状况的动物模型中验证这些靶点和技术(第二年)，并应用基础和动物模型研究的结果在有针对性的人类炎症性疾病中进行初步研究(第三年)。这项转化性的临床应用研究将涉及一个由来自3所大学和美国环境保护局5所学院的9个部门和7个中心的60名研究人员组成的多学科互动小组。这一组织良好的规划过程将产生临床相关的结果，这些结果可以迅速优化，以应用于多个器官中的一些重要炎症性疾病。这个项目将创建一个新的项目，涉及以前没有合作过的调查人员，同时建立在机构优势和方案倡议的基础上。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. DESCRIPTION (provided by applicant): Although significant strides have been made toward better understanding the mechanisms of immunoregulation and genetic susceptibility of chronic inflammatory disorders, includingimmune-mediatedarthritis, diabetes, inflammatory bowel diseases, systemic lupus erythematosus (SLE),glomerulonephritis, vasculitis, atherosclerosis and asthma, a major impediment to their diagnosis and clinical management is the inability to easily determine and quantify the activity and extent of disease involving in accessible internal organs. Moreover, current techniques cannot identify subclinical inflammation that predicts rapid recurrence of symptoms after inducing remission or the on set of disease in high risk individuals. Histologic diagnosis and assessment of disease activity in the intestine, lung, liver, kidney, joint, blood vessels, thyroid and brain, require invasive endoscopic, percutaneous or even open surgical biopsy, which entail considerable discomfort and risk. Our goal is to develop noninvasive methods to determine the location and intensity of inflammation in inaccessible organs of patients with several inflammatory diseases by applying basic knowledge of the mechanisms of vascular endothelial/ effector inflammatory cell interactions, activation of innate and acquired immune cells, vascular permeability and neovascularization to novel imaging techniques. Our studies will focus on Crohn's disease, ulcerative colitis, SLE, anti-neutrophil cytoplasmic antibody (ANCA)-mediated vasculitis and atherosclerosis because interdisciplinary research programs that encompass basic mechanistic, animal model and clinical investigations in these disorders exist in our institution, each are multiorgan conditions, and these diseases are prototypes of T lymphocyte, antibody/complement, neutrophil and macrophage-mediated disorders, respectively. Results from these focused studies will therefore be applicable to all of the previously mentioned inflammatory conditions. The following Specific Aims will approach this goal: 1. Develop an administrative structure that will plan and coordinate activities and promote effective interactions and communication among a multidisciplinary group of investigators. 2. Organize topic-driven workshops promoting interactions between local investigators and external experts to define the optimal molecular targets, detection techniques and clinical applications for determining the extent and activity of inflammation in a variety of organs and disease processes. 3. Support pilot studies to define molecular targets (1st year), optimize imaging and molecular/biochemical/immunologic techniques (1st and 2nd years), validate these targets and techniques in animal models of inflammatory conditions in diverse organs (2nd year), and perform pilot studies in targeted human inflammatory diseases applying the results of the basic and animal model studies (3rd year). This translational, clinically applied research will involve a multidisciplinary, interactive group of >60 investigators derived from 9 departments and 7 centers in 5 schools of 3 universities and the Environmental Protection Agency. This well organized planning process will result in clinically relevant outcomes that can be quickly optimized for application to a number of important inflammatory diseases in multiple organs. This project will create a new program involving investigators who have not previously worked together, while building on institutional strengths and programmatic initiatives.