THREE DIMENSIONAL PROJECTION ENVIRONMENT FOR MOLECULAR DESIGN AND SURGICAL SIMU

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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.