Concurrent ultrasound & molecular evaluation of a lymphatic malformation model

描述(申请人提供)：淋巴管畸形(LMS)是影响1：3500儿童的先天性病变，通常在儿童早期表现，并与重大疾病有关，包括视力丧失、呼吸衰竭和反复感染。虽然LMS越来越多地在产前被发现，引发围产期干预和对受影响婴儿的密集支持，但它们往往难以接受手术和药物治疗。值得注意的是，对LMS的病理生物学了解甚少，控制反应和复发的过程也没有被研究过。在美国，大多数LM患者使用2D磁共振成像(MRI)进行监测，这对儿童来说是昂贵、耗时和需要麻醉的。因此，MRI不能用于实时、快速、连续监测儿童LM患者的治疗反应。因此，迫切需要开发新的非侵入性监测策略。基于超声的成像具有满足这一需求的潜力，因为它快速、廉价，并且可以用已经广泛可用的设备来实施。我们最近从LM患者样本(LMSCs)中分离出一种新的干细胞样群。移植到免疫缺陷小鼠体内后，LMSCs在分子、超声和MRI下形成与临床LMS相似的病变。我们建议使用这种LM小鼠模型来开发基于超声的LMS诊断和监测工具，最终目标是测试和翻译新的治疗方法。具体地说，我们将评估三种声学方法的同时使用：显微超声、对比增强超声(CEUS)和谐波运动成像(HMI)，这两种方法都用于LMS的开发和现有药物的试点治疗之后。我们将把获得的数据与平行磁共振成像的结果进行比较，并将结果与分子和组织学特征相关联。这些临床前研究具有很高的创新性和临床相关性，可以为新的治疗方法的快速转化提供一个重要的平台。我们的总体目标是提高我们严格评估新的LM疗法的能力，整合临床相关成像和对LM发病机制的理解。这样的做法将极有可能改善对这一儿童孤儿疾病的护理。好了！

DESCRIPTION (provided by applicant): Lymphatic malformations (LMs) are congenital lesions affecting 1:3500 children usually manifesting in early childhood, and are associated with significant morbidities, including vision loss, respiratory failure, and repetitive infections. Whie LMs are increasingly identified antenatally, triggering perinatal interventions and intensive support of affected babies, they are frequently refractory to surgical and medical treatment. Notably, the pathobiology of LMs is poorly understood, and the processes governing response and recurrence have not been studied. In the United States, most LM patients are monitored with 2D magnetic resonance imaging (MRI), which is expensive, time-consuming, and requires anesthesia in children. MRI is therefore not feasible for real-time, rapid, serial monitoring of treatment responses in pediatric LM patients. Thus, the development of new noninvasive monitoring strategies is urgently needed. Ultrasound-based imaging has the potential to address this need, as it is quick, inexpensive, and can be implemented with equipment already widely available. We have recently isolated a novel stem cell-like population from LM patient samples (LMSCs). LMSCs form lesions which phenocopy clinical LMs, molecularly and by ultrasound and MRI, after implantation into immunodeficient mice. We propose to use this LM mouse model to develop an ultrasound-based diagnostic and monitoring tool for LMs, with the ultimate goal of testing and translating novel therapies. Specifically, we will evaluate the concurrent use of three acoustic methodologies: microultrasound, contrast- enhanced ultrasound (CEUS), and harmonic motion imaging (HMI), both on developing LMs and after pilot treatments with current agents. We will compare the data obtained with the results of parallel MR imaging, and correlate results with molecular and histologic characteristics. These pre-clinical studies are highly innovative and clinically relevant, and could provide a crucial platform for the rapid translation f new therapeutic approaches. Our overall goal is to enhance our ability to rigorously evaluate novel LM therapies, integrating clinically relevant imaging and a mechanistic understanding of LM pathogenesis. Such an approach would have high potential for improving care for this orphan disease of childhood. !