Quantification and monitoring inflammation in IBD with Molecular Ultrasound

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，在美国影响约140万患者，其中包括许多儿童和年轻人。它的特点是肠壁广泛的炎症改变，在肠壁血管内皮细胞上过度表达分子炎症标志物，如P-选择素。由于IBD具有多次复发的慢性和较长的治疗阶段，包括与主要副作用相关的免疫抑制剂和-调节剂等药物，因此定期和准确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，因此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，已经满足了许多要求，因为1)它以相对较低的成本广泛可用，2)它不会使患者暴露于电离辐射

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.