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; 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）：包括克罗恩病和溃疡性结肠炎在内的炎症性肠病（IBD）影响美国约140万患者，包括许多儿童和年轻人。它的特征是肠壁上有广泛的炎症变化，分子炎症标志物（例如p-选择蛋白）在肠壁上的血管内皮细胞上的过度表达。由于IBD的长期繁殖以及与重大副作用相关的免疫抑制剂和 - 调节剂等药物的长期复发和长期治疗阶段，因此对疾病活性的定期和准确监测至关重要。由于需要多次后续考试，因此通常多年来，监测应该是无创的，最重要的是患者友好。当前，尚不可满足所有这些要求的简单技术。超声（美国）是一种无创的成像方法，已经满足许多要求，因为1）它以相对较低的成本广泛使用，而2）它不会使患者暴露于电离辐射 （这对于重复考试非常重要，特别是在儿童和年轻人中）。但是，当前的美国技术缺乏准确量化肠壁炎症的敏感性和特异性。此外，与我们一起成像肠子可能具有挑战性（例如，肠内大量的空间取向，可能的伪影从腔内气体，运动等）。在这项赠款建议中，我们将我们的优势与分子成像的优势结合在一起，并使用新型的对比微泡制定了分子成像策略，从而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，该微泡针对炎症标记P-选择蛋白（P-MB）的目标是将US转变为将炎症监测为临床试验。在特定目标1中，我们将使用新型的临床级P-MB测试分子，以在鼠IBD模型中对分子水平的炎症进行成像和定量。在特定的目标2中，我们将使用离体分析作为黄金标准将其监测IBD炎症的潜力与18FDG-PET-CT和DCE-MRI进行比较。在特定的目标3中，我们将在猪IBD模型中将成像方法从小动物转化为临床翻译的进一步一步。 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.我们还将开发和测试肠道中新型的实时融合MRI/分子成像方法，最终在将分子成像转化为诊所时，应对预期的挑战，例如需要对大量图像进行图像以获得发炎的肠段的代表性图像，并在空间方向上以及在巨大的领域中降低了弓形领域的空间方向，并可以在巨大的彩头中降低弓形的范围，从而降低了弓箭的范围，并且可以从肠子内进行综合，并且可以从肠子范围内进行，并且可以从视图上进行绘制。腔内气体和运动。在成功完成研究目标之后，我们预计这种患者友好，无创和定量成像技术将快速转化为诊所，以改善IBD患者的临床管理和结果。