THREE DIMENSIONAL PROJECTION ENVIRONMENT FOR MOLECULAR DESIGN AND SURGICAL SIMU

用于分子设计和手术模拟的三维投影环境

• 批准号: 7956354
• 负责人: ERIC WICKSTROM
• 金额: $ 0.08万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956354
• 关键词: Acute; Affect; Affinity; Antidotes; Area; Binding; Biological; Biological Products; Biomedical Research; Breast; Characteristics; Chemicals; Complex; Computer Retrieval of Information on Scientific Projects Database; Computer Simulation; Data; Defensins; Development; Diagnostic; Disease; Docking; Environment; Exposure to; Feedback; Funding; Future; Grant; Hemorrhage; High Performance Computing; Image; Infection; Injury; Institution; Kinetics; Libraries; Ligand Binding; Ligands; Link; Location; Magnetic Resonance Imaging; Measurement; Measures; Molecular; Molecular Models; Neck Neoplasms; Nucleic Acids; Oncogenes; Operative Surgical Procedures; Organ; Pathway interactions; Patients; Positron-Emission Tomography; Proteins; Research; Research Design; Research Personnel; Resources; Roentgen Rays; Scanning; Shock; Site; Source; Structure; Surgeon; System; Tactile; Testing; Three-Dimensional Imaging; Time; Tissues; Touch sensation; Trauma; Ultrasonography; United States National Institutes of Health; X-Ray Computed Tomography; analog; anthrax toxin; base; design; drug candidate; haptics; improved; inhibitor/antagonist; killings; macromolecule; molecular modeling; protein aminoacid sequence; single photon emission computed tomography; small molecule; visual feedback; weapons

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 背景：战场伤亡人员多部位、多器官遭受复杂创伤。接触化学和生物制剂也是一个令人担忧的问题。许多伤员出现休克、内出血和感染的症状。哪个问题会首先杀死病人？外科医生如何可视化受伤的位置、种类、程度和严重程度？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、超声波 (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，旨在识别急性损伤和疾病的部位。我们率先设计、合成和测试用于蛋白质和核酸基因产品无创成像的试剂，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成像剂将描绘出最严重的创伤或疾病的部位。目的：三维成像系统，1）将基因产物成像数据叠加在解剖结构上，并提供触觉和感觉（触觉）反馈，以便外科医生在打开之前评估受影响器官的各种方法，2）通过动力学途径的触觉和感觉反馈将配体与大分子对接，以确定最有利的候选药物，并剔除无前途的药物 候选人。具体目标1：我们将测试三维触觉系统将基因产物成像与解剖成像融合的能力，以探索最佳的计算机手术方法。我们将把解剖和基因产物成像与实时触摸和感觉（触觉反馈）联系起来，以便为规划外科手术的“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抑制剂分子模型（例如防御素和较小的类似物）与目标大分子（例如炭疽毒素）对接的能力。使用触觉反馈和对沿动力学路径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：我们将评估两种替代手术策略切除乳腺/颈部肿瘤的可行性，该肿瘤通过 CT/MRI 进行解剖学定义，并通过特征性癌症基因产物的放射成像进行分子学定义。具体目标 2：我们将扫描所选肽序列的计算机文库，以鉴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通过触觉反馈手动对接，使我们能够识别容易且紧密结合的药剂设计，同时从计算机命中列表中剔除效率低下的结构。然后，我们将合成三种最有前途的试剂，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：包括基因产物成像的触觉成像系统是未来全息手术室的先驱。此外，触觉分子设计组件将允许更快速地开发解毒剂或相互作用分子，以抑制或中和针对美军的敌方化学和/或生物武器。我们预测该系统将显着提高战场伤亡人员的生存率。