THREE DIMENSIONAL PROJECTION ENVIRONMENT FOR MOLECULAR DESIGN AND SURGICAL SIMU

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 背景：战场伤员在多个部位和器官遭受复杂创伤。接触化学和生物制剂也是一个非常令人担忧的问题。许多伤者出现休克、内出血和感染。哪个问题会先杀死病人？外科医生如何能直观地看到受伤的位置、种类、程度和严重性？在战场之外，临床医生如何通过成像组织中的基因产物表达来可视化疾病的部位和生物学基础？X射线、超声(US)、计算机断层扫描(CT)和磁共振成像(MRI)所看到的解剖细节并不能揭示引发和调节疾病的潜在基因产物。分子诊断，特别是非侵入性显像剂，正在被设计用来识别急性损伤和疾病的部位。我们率先设计、合成和测试了蛋白质和核酸基因产品的非侵入性成像试剂，以识别患者的疾病区域。我们断言，通过正电子发射断层扫描(PET)、SPECT或MRI添加蛋白质和核酸的基因产物显像剂将描绘出最严重的创伤或疾病的位置。目的：一种三维成像系统，它1)将基因产物成像数据覆盖在解剖结构上，并提供触觉反馈，以便外科医生在打开之前评估对受影响器官的各种方法；2)将配体与具有动力学途径的触觉反馈的大分子对接，以识别最有利的候选药物，并淘汰不受欢迎的候选药物。具体目标1：我们将测试三维触觉系统融合基因产物成像和解剖成像的能力，以探索硅胶手术的最佳方法。我们将把解剖学和基因产品成像与实时触摸和感觉(触觉反馈)联系起来，以便为计划手术过程的“操作者”提供触觉和视觉反馈。具体目标2：我们将测试三维触觉系统将防御素和较小类似物等抑制剂的分子模型与炭疽毒素等目标大分子对接的能力。使用触觉反馈和对运动路径上遇到的障碍进行定量测量，将能够剔除不利的设计。研究设计：具体目标1：我们将评估两种可供选择的手术策略的可行性，以切除由CT/MRI确定的解剖学上的乳腺/颈部肿瘤，以及通过放射成像确定的一种特有的癌症基因产物。具体目标2：我们将扫描选定的多肽序列的电子文库，以确定潜在的炭疽毒素小分子抑制剂。与炭疽毒素结合的潜在配体将与触觉反馈手动对接，使我们能够识别容易和紧密结合的试剂设计，同时从In Silico Hit List中剔除低效结构。然后，我们将合成三种最有希望的试剂，并在工作台上测量它们与炭疽毒素的实际结合亲和力。相关性：包括基因产品成像在内的触觉成像系统是未来全息外科套件的先驱。此外，触觉分子设计组件将允许更快地开发解毒剂或相互作用的分子，以抑制或中和针对美国军队的敌人化学和/或生物武器。我们预测，该系统将显着提高战场伤员的存活率。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background: Battlefield casualties suffer complex wounds in multiple sites and organs. Exposure to chemical and biological agents is also a great concern. Many casualties present with shock, internal bleeding, and infection. Which problem can kill the patient first? How can surgeons visualize the locations, varieties, extent, and seriousness of injuries sustained? Off the battlefield, how can clinicians visualize sites and biological basis of disease by imaging gene product expression in tissues? Anatomical details seen by X-rays, ultrasound (US), computerized tomography (CT), and magnetic resonance imaging (MRI) do not reveal the underlying gene products that initiate and regulate disease. Molecular diagnostics, particularly noninvasive imaging agents, are being designed to identify sites of acute injury and disease. We have pioneered the design, synthesis, and testing of agents for noninvasive imaging of protein and nucleic acid gene products that identify areas of disease in patients. We assert that the addition of gene product imaging agents for proteins and nucleic acids by positron emission tomography (PET), SPECT, or MRI will delineate the sites of the most serious trauma or disease. Objective: A three-dimensional imaging system that 1) overlays gene product imaging data on anatomical structures and provides touch and feel (haptic) feedback in order to allow surgeons to assess a variety of approaches to the affected organs prior to opening, and 2) docks ligands with macromolecules with touch and feel feedback of the kinetic pathway in order to identify the most favorable drug candidates, and cull unpromising candidates. Specific Aim 1: We will test the ability of the three-dimensional haptic system to fuse gene product imaging with anatomical imaging for the purpose of exploring optimal surgical approaches in silico. We will link anatomical and gene product imaging with real time touch and feel (haptic feedback) in order to provide tactile and visual feedback to the "operator" planning a surgical procedure. Specific Aim 2: We will test the ability of the three-dimensional haptic system to dock molecular models of inhibitors, such as defensin and smaller analogs, with target macromolecules, such as anthrax toxin. The use of haptic feedback and quantitative measurements of obstacles encountered along the kinetic pathway will enable culling of unfavorable designs. Study Design: Specific Aim 1: We will assess the feasibility of two alternate surgical strategies for excising a breast/neck tumor that is defined anatomically by CT/MRI, and molecularly by radioimaging of a characteristic cancer gene product. Specific Aim 2: We will scan in silico libraries of selected peptide sequences to identify potential small molecule inhibitors of anthrax toxin. Potential ligands for binding to anthrax toxin will be docked manually with haptic feedback, allowing us to identify agent designs that bind readily and tightly, while culling inefficient structures from the in silico hit list. We will then synthesize the three most promising agents and measure their actual binding affinities to anthrax toxin on the bench. Relevance: Haptic imaging systems that include gene product imaging are the forerunners of the holographic surgical suites of the future. Furthermore, the haptic molecular design component will permit more rapid development of antidotes or interacting molecules that will either inhibit or neutralize enemy chemical and/or biological weapons aimed at US forces. We predict that this system will significantly improve the survival of battlefield casualties.