Concurrent ultrasound & molecular evaluation of a lymphatic malformation model

描述（由申请方提供）：淋巴管畸形（LM）是一种影响1：3500儿童的先天性病变，通常在幼儿期出现，并与显著的发病率相关，包括视力丧失、呼吸衰竭和反复感染。虽然LM越来越多地在产前被发现，引发围产期干预和受影响婴儿的强化支持，但它们通常难以接受手术和药物治疗。值得注意的是，LM的病理生物学知之甚少，并且尚未研究控制响应和复发的过程。在美国，大多数LM患者使用2D磁共振成像（MRI）进行监测，这是昂贵的，耗时的，并且需要麻醉儿童。因此，MRI不适用于对儿童LM患者的治疗反应进行实时、快速、连续监测。因此，迫切需要开发新的无创监测策略。基于超声的成像有可能满足这一需求，因为它快速，廉价，并且可以使用已经广泛使用的设备来实现。我们最近从LM患者样本（LMSC）中分离出一种新的干细胞样群体。LMSC在植入免疫缺陷小鼠后形成病变，其在分子上以及通过超声和MRI表现为临床LM。我们建议使用这种LM小鼠模型开发一种基于超声的LM诊断和监测工具，最终目标是测试和翻译新的疗法。具体而言，我们将评估同时使用三种声学方法：微超声、造影剂增强超声（CEUS）和谐波运动成像（HMI），无论是在开发LM时还是在使用当前药物进行试点治疗后。我们将比较所获得的数据与并行MR成像的结果，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关键平台。我们的总体目标是提高我们的能力，严格评估新的LM疗法，整合临床相关的成像和LM发病机制的理解。这种方法将有很大的潜力，以改善这种孤儿疾病的儿童护理。!

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. !