In Vivo Laser Capture Microdissection

 描述(由申请者提供)：我们描述体细胞DNA变化的能力有望给医学带来革命性的变化，使我们能够预测疾病的发生/发展，并以前所未有的精度制作个性化的药物疗法。基因组学的这种变革性潜力提高了从人体中识别和分离最有诊断价值的组织的重要性。今天，大多数组织是通过手术或标准的活组织检查来提取的。不幸的是，这些方法是侵入性的，昂贵，耗时，而且不精确。由于肉眼检查不能识别微观组织特征，而且切除很粗糙，因此缺乏敏感性和特异性。目前的切除方法要么无法对关键的微观疾病进行采样，要么无法提取正常组织和疾病组织的混合物，从而使下游的基因组分析复杂化。在这项提案中，我们将通过开发一种名为体内激光捕获显微切割(IVLCM)的新技术来解决这一领域的关键障碍。IVLCM使用微创设备立即在活着的患者身上进行全面的显微镜检查，识别具有疾病微观证据的组织，并将目标组织激光捕获到设备上。在将设备从体内移除后，对组织进行处理，以进行随后的遗传、分子和组织病理学分析。通过使组织获取更准确和更容易获得，IVLCM将允许基因组诊断在临床实践中常规使用，扩大精确医学的覆盖范围。这笔赠款的临床重点是巴雷特食道(BE)，这是一种癌症前期疾病，在筛查和监测方面没有满足临床需求，可以通过一种改进的工具对变异组织进行精确分离和基因分型来解决。我们建议的BE解决方案是一种捆绑的IVLCM药丸，可以被未服用镇静剂的受试者吞咽，使其比标准的内窥镜活检更容易、更便宜。随着技术的发展，我们将在临床研究中验证胶囊IVLCM用于BE监测和筛查的能力，这些临床研究将IVLCM提取的组织的基因组分析与传统的活组织检查和使用盲法采样筛查设备获取的细胞的基因组分析进行比较。

 DESCRIPTION (provided by applicant): Our ability to characterize somatic DNA alterations promises to revolutionize medicine, allowing us to predict disease onset/progression and craft individualized pharmacologic therapies with an unprecedented level of precision. This transformative potential of genomics has elevated the importance of identifying and isolating the most diagnostically useful tissue from the body. Today, most tissues are extracted via surgery or standard biopsy. Unfortunately, these methods are invasive, expensive, time-consuming, and imprecise. Because macroscopic inspection cannot identify microscopic tissue features and excision is crude, both sensitivity and specificity are lacking. Current excisional approaches either fail to sample critical microscopic disease or extract a composite of normal and diseased tissues, complicating downstream genomic analysis. In this proposal, we will address this key barrier in the field by developing a new technology termed in vivo laser capture microdissection (IVLCM). IVLCM uses a minimally invasive device to at once conduct comprehensive microscopy in the living patient, identify tissue with microscopic evidence of disease, and laser capture the targeted tissues onto the device. After the device is removed from the body, the tissues are processed for subsequent genetic, molecular and histopathologic analysis. By making tissue procurement more accurate and accessible, IVLCM will allow genomic diagnostics to be used routinely in clinical practice, expanding the reach of precision medicine. The clinical focus of this grant is Barrett's esophagus (BE), a precancerous condition with unmet clinical needs in screening and surveillance that can be addressed by an improved tool for precise isolation and genotyping of aberrant tissues. Our proposed solution for BE is a tethered IVLCM pill that can be swallowed by unsedated subjects, making it much easier and less expensive to administer than standard endoscopic biopsy. Following development of the technology, we will validate the capabilities of capsule IVLCM for BE surveillance and screening in clinical studies that compare genomic analysis of IVLCM-extracted tissues to that of conventional biopsies and cells acquired using a blind-sampling screening device.