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: 8364287
• 负责人: ERIC WICKSTROM
• 金额: $ 0.1万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8364287
• 关键词: Acute; Affect; Affinity; Antidotes; Area; Binding; Biological; Biological Products; Biomedical Research; Breast; Characteristics; Chemical Agents; Chemicals; Complex; Computer Simulation; Data; Defensins; Development; Diagnostic; Disease; Docking; Environment; Exposure to; Feedback; Funding; Future; Grant; Hemorrhage; High Performance Computing; Image; Infection; Injury; Kinetics; Libraries; Ligand Binding; Ligands; Link; Location; Magnetic Resonance Imaging; Measurement; Measures; Molecular; Molecular Models; National Center for Research Resources; Neck Neoplasms; Nucleic Acids; Oncogenes; Operative Surgical Procedures; Organ; Pathway interactions; Patients; Positron-Emission Tomography; Principal Investigator; Proteins; Research; Research Design; Research Infrastructure; 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; cost; 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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 背景：战场伤亡人数在多个地点和器官中遭受了复杂的伤口。接触化学和生物剂也是一个很大的问题。许多人员伤亡都充满了冲击，内部出血和感染。哪个问题可以首先杀死患者？外科医生如何能看到受伤的位置，品种，程度和严重性？在战场上，临床医生如何通过对组织中的基因产物表达进行成像，如何可视化疾病的部位和生物学基础？ X射线，超声（US），计算机层析成像（CT）和磁共振成像（MRI）看到的解剖细节并未揭示启动和调节疾病的潜在基因产物。分子诊断，尤其是无创成像剂，旨在识别急性损伤和疾病的部位。我们开创了对蛋白质和核酸基因产物的非侵入性成像的设计，合成和测试，这些蛋白质和核酸基因产物鉴定了患者的疾病区域。我们断言，通过正电子发射断层扫描（PET），SPECT或MRI添加基因产物成像为蛋白质和核酸，将描绘出最严重的创伤或疾病的部位。 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，以探索硅中的最佳手术方法。我们将将解剖和基因产品成像与实时触摸和感觉（触觉反馈）联系起来，以便向计划手术程序的“操作员”提供触觉和视觉反馈。具体目的2：我们将测试三维触觉系统与靶标大分子（例如炭疽毒素）的抑制剂（例如防御素和较小的类似物）的分子模型的能力。在动力学途径遇到的障碍物的触觉反馈和定量测量中，将淘汰不利的设计。研究设计：具体目的1：我们将评估两种替代手术策略的可行性，以切除乳腺/颈部肿瘤，该乳腺/颈部肿瘤是通过CT/MRI解剖学定义的，并通过分子通过放射现象的特征性癌症基因产物进行分子。具体目标2：我们将在选定肽序列的硅库中扫描，以鉴定炭疽毒素的潜在小分子抑制剂。与触觉反馈的潜在配体与炭疽毒素结合，可以用触觉反馈对接，从而使我们能够识别易于粘合的剂设计，同时从硅的命中列表中剔除效率低下的结构。然后，我们将综合三种最有前途的药物，并测量其实际的结合亲和力与长凳上的炭疽毒素。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手术套房的先驱。此外，触觉分子设计组件将允许更快地发展解毒剂或相互作用的分子，这些分子将抑制或中和针对美军的敌方化学和/或生物武器。我们预测，该系统将大大改善战场伤亡的生存。