Quantification and monitoring inflammation in IBD with Molecular Ultrasound

用分子超声定量和监测 IBD 炎症

• 批准号: 8880188
• 负责人: Juergen Karl Willmann
• 金额: $ 45.68万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-05 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8880188
• 关键词: Abdomen; Acoustics; Address; Adverse effects; Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Binding; Biological Assay; Child; Chronic; Clinic; Clinical; Clinical Management; Clinical Trials; Colitis; Contrast Media; Crohn' s disease; Data; Data Set; Development; Disadvantaged; Disease; Disease model; Dose; Electromagnetics; Family suidae; Foundations; Functional Imaging; Gases; Gastrointestinal tract structure; Glucose; Goals; Gold; Histology; Histopathology; Human; Image; Imagery; Imaging Techniques; Immunomodulators; Immunosuppressive Agents; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Lead; Ligands; Magnetic Resonance Imaging; Measures; Microbubbles; Modality; Modeling; Molecular; Monitor; Morphologic artifacts; Motion; Mus; Outcome; P-Selectin; Patients; Pharmaceutical Preparations; Phase; Positioning Attribute; Positron-Emission Tomography; Radiation; Relapse; Relative (related person); Reporting; Research; Research Proposals; Sensitivity and Specificity; Signal Transduction; Space Perception; System; Techniques; Technology; Terminal Ileitis; Testing; Time; Translating; Translations; Ulcerative Colitis; Ultrasonography; United States; Vascular Endothelial Cell; X-Ray Computed Tomography; base; contrast enhanced; cost; design; diagnostic accuracy; follow-up; imaging modality; improved; in vivo; in vivo imaging; inflammatory marker; irradiation; meetings; molecular imaging; molecular marker; mouse model; non-invasive imaging; non-invasive monitor; novel; overexpression; particle; quantitative imaging; reconstruction; sensor; young adult

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) which includes Crohn's disease and ulcerative colitis affects about 1.4 million patients in the United States, including many children and young adults. It is characterized by extensive inflammatory changes in the bowel wall with overexpression of molecular inflammation markers such as P- selectin on vascular endothelial cells in the bowel wall. Due to the chronicity of IBD with multipl relapses and long treatment phases including drugs such as immunosuppressants and -modulators that are associated with major side-effects, regular and accurate monitoring of the disease's activity is of paramount importance. Since multiple follow-up exams are needed, often over many years, monitoring should be noninvasive and, above all, patient-friendly. Currently, a simple technique that meets all these requirements is not available. Ultrasound (US) is a non-invasive imaging approach that already meets many of those requirements because 1) it is widely available at relatively low cost, and 2) it does not expose patients to ionizing irradiation (which is very important for repetitive examinations in particular in children and young adults). However, current US technology lacks the sensitivity and specificity to accurately quantify inflammation in the bowel wall. Furthermore, imaging the bowel with US can be technically challenging (e.g., spatial orientation within the large volume of the bowel, possible artifacts fro intraluminal gas, motion, etc). In this grant proposal we combine the advantages of US with those of molecular imaging and develop a molecular US imaging strategy using novel contrast microbubbles that allow inflammation imaging at the molecular level. We have designed a clinical grade microbubble that targets the inflammation marker P-selectin (P-MB) with the goal to transition molecular US for monitoring inflammation into clinical trials. In specific aim 1, we will test molecular US using novel clinical grade P-MB for imaging and quantification of inflammation at the molecular level in a murine IBD model. In specific aim 2, we will compare its potential for monitoring inflammation in IBD to 18FDG-PET-CT and DCE-MRI, using ex vivo assays as the gold standard. In specific aim 3, we will translate our imaging approach from small to large animals in a porcine IBD model as a further step towards clinical translation. Critical data on the feasibility of an optimized molecular US imaging approach in porcine models of IBD (including terminal ileitis and colitis) will be obtained including the opportunity to correate in vivo imaging signals with ex vivo P- selectin expression levels and assessing optimal dosing of novel P-MB in pigs before eventual translation of our novel imaging approach into first-in-human clinical trials. We will also develop and test a novel real-time fused MRI/molecular US imaging approach of the bowel, addressing anticipated challenges when eventually translating molecular US imaging into the clinic, such as the need to image a large volume to obtain representative images of inflamed bowel segments, along with spatial orientation to reliably localize inflamed bowel segments within the large field of view of the bowel, as well as the need to reduce possible artifacts from intraluminal gas and motion. Following successful completion of our research aims, we anticipate rapid translation of this patient-friendly, non-invasive and quantitative imaging technique into the clinic to improve clinical management and outcome of patients with IBD.

描述（由申请人提供）：炎症性肠病（IBD），包括克罗恩病和溃疡性结肠炎，影响美国约140万患者，包括许多儿童和年轻人。其特征在于肠壁中广泛的炎性变化，伴有肠壁中血管内皮细胞上的分子炎症标志物如P-选择素的过度表达。由于IBD的慢性性，其具有多次复发和长的治疗阶段，包括与主要副作用相关的药物如免疫抑制剂和β-调节剂，因此定期和准确地监测疾病的活性是至关重要的。由于需要多次随访检查，通常需要多年，因此监测应该是无创的，最重要的是对患者友好。目前，还没有一种简单的技术可以满足所有这些要求。超声（US）是一种非侵入性成像方法，已经满足了许多这些要求，因为1）它以相对低的成本广泛可用，以及2）它不会使患者暴露于电离辐射 （这对于重复检查非常重要，特别是在儿童和年轻人中）。然而，目前的美国技术缺乏准确量化肠壁炎症的灵敏度和特异性。此外，用US对肠进行成像在技术上可能具有挑战性（例如，肠的大体积内的空间取向、来自管腔内气体、运动等的可能伪影）。在这项资助提案中，我们联合收割机了US与分子成像的优势，并开发了一种分子US成像策略，使用新型造影剂微泡，允许在分子水平上进行炎症成像。我们设计了一种临床级微泡，其靶向炎症标记物P-选择素（P-MB），目的是将用于监测炎症的分子US过渡到临床试验。在具体目标1中，我们将使用新型临床级P-MB测试分子US，用于在小鼠IBD模型中在分子水平上成像和定量炎症。在具体目标2中，我们将使用离体测定作为金标准，将其监测IBD炎症的潜力与18 FDG-PET-CT和DCE-MRI进行比较。在具体目标3中，我们将在猪IBD模型中将我们的成像方法从小型动物转化为大型动物，作为临床转化的进一步步骤。将获得关于优化的分子US成像方法在IBD（包括末端回肠炎和结肠炎）的猪模型中的可行性的关键数据，包括将体内成像信号与离体P-选择素表达水平相关联的机会，以及在我们的新型成像方法最终转化为首次人体临床试验之前评估新型P-MB在猪中的最佳剂量。我们还将开发和测试一种新型的实时融合MRI/分子US肠成像方法，解决最终将分子US成像转化为临床时的预期挑战，例如需要对大体积进行成像以获得发炎肠段的代表性图像，沿着空间定向以可靠地在肠的大视野内定位发炎肠段，以及需要减少来自管腔内气体和运动的可能的伪影。在成功完成我们的研究目标后，我们预计这种患者友好，非侵入性和定量成像技术将快速转化为临床，以改善IBD患者的临床管理和结局。