Concurrent ultrasound & molecular evaluation of a lymphatic malformation model

描述（由申请人提供）：淋巴畸形（LMs）是影响1:3500儿童的先天性病变，通常表现在儿童早期，并与显著的发病率相关，包括视力丧失、呼吸衰竭和重复感染。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强化支持，但它们往往难以手术和药物治疗。值得注意的是，LMs的病理生物学知之甚少，控制反应和复发的过程尚未研究。在美国，大多数LM患者使用二维磁共振成像（MRI）进行监测，这是昂贵的，耗时的，并且儿童需要麻醉。因此，MRI对于儿童LM患者治疗反应的实时、快速、连续监测是不可行的。因此，迫切需要开发新的无创监测策略。基于超声波的成像有可能满足这一需求，因为它快速、廉价，并且可以在已经广泛使用的设备上实施。我们最近从LM患者样本（LMSCs）中分离出一种新的干细胞样群体。植入免疫缺陷小鼠后，LMSCs形成病变，通过分子、超声和MRI表现临床LMs。我们建议利用这种LM小鼠模型来开发一种基于超声的LM诊断和监测工具，最终目的是测试和转化新的治疗方法。具体来说，我们将评估三种声学方法的同时使用：微超声、对比增强超声（CEUS）和谐波运动成像（HMI），这两种方法都适用于发展中的LMs和使用现有药物进行试点治疗后。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高度创新性和临床相关性，可以为新治疗方法的快速转化提供重要平台。我们的总体目标是提高我们严格评估新型LM疗法的能力，整合临床相关影像学和对LM发病机制的理解。这种方法在改善对这种儿童孤儿疾病的护理方面具有很大的潜力。！

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. !