Quantification and monitoring inflammation in IBD with Molecular Ultrasound

描述(申请人提供)：炎症性肠病(IBD)，包括克罗恩病和溃疡性结肠炎，在美国影响大约140万患者，包括许多儿童和年轻人。其特点是肠壁广泛的炎性改变，肠壁血管内皮细胞上P-选择素等分子炎症标志物的过度表达。由于IBD是一种慢性疾病，具有多次复发和治疗周期长的特点，包括免疫抑制剂和调节剂等与主要副作用相关的药物，因此定期和准确地监测疾病的活动至关重要。由于需要多次随访检查，通常需要多年，监测应该是非侵入性的，最重要的是，对患者友好。目前，还没有一种满足所有这些要求的简单技术。超声(US)是一种非侵入性成像方法，已经满足了其中许多要求，因为1)它以相对较低的成本广泛使用，2)它不会使患者暴露在电离辐射中 (这对于重复考试非常重要，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敏感性和特异性。此外，使用US对肠道进行成像可能在技术上具有挑战性(例如，大肠体积内的空间定位、腔内气体可能产生的伪影、运动等)。在这项拨款提案中，我们结合了超声和分子成像的优势，开发了一种使用新型对比微泡的分子超声成像策略，允许在分子水平上进行炎症成像。我们设计了一种针对炎症标志物P-选择素(P-MB)的临床级微泡，目的是将用于监测炎症的分子US转化为临床试验。在具体目标1中，我们将使用新的临床级别P-MB来测试分子超声，以在小鼠IBD模型中在分子水平上对炎症进行成像和定量。在具体目标2中，我们将以体外试验为金标准，将其在监测IBD炎症方面的潜力与18FDG-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动物移植到大动物，作为临床移植的进一步步骤。在猪的IBD模型(包括终末期回肠炎和结肠炎)中，优化的分子超声成像方法的可行性将获得关键数据，包括将体内成像信号与体外P-选择素表达水平进行关联的机会，以及在最终将我们的新成像方法转化为人类首个临床试验之前，评估新型P-MB在猪身上的最佳剂量。我们还将开发和测试一种新的实时融合的磁共振成像/分子超声肠道成像方法，以解决最终将分子超声成像转移到临床时预期的挑战，例如需要对大容量图像进行成像以获得发炎肠段的代表性图像，以及需要进行空间定位以可靠地定位发炎肠段在肠的大视野内，以及需要减少腔内气体和运动可能产生的伪影。随着我们的研究目标的成功完成，我们期待着将这种患者友好、非侵入性和定量成像技术迅速转化为临床，以改善IBD患者的临床管理和预后。

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.