Submission of proposals
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2) Pancrazio, J. J. (Editor) 2001. Cell-based biosensors. Special issue of Biosensors and Bioelectronics. 16(7-8). 3) van der Schalie, W. H., Reuter, R., Shedd, T. R., and Knechtges, P. L. 2002. Environmental sentinel biomonitors: integrated response systems for monitoring toxic chemicals. In: Jensen, J.L. and Burggraf, L.W., Eds., Proceedings of the Conference on Chemical and Biological Early Warning Monitoring for Water, Food, and Ground, Conference 4575, Society of Photo-Optical Instrumentation Engineers, Bellingham, WA. pp 23-31. KEYWORDS: Air Toxicity Monitoring, Toxic Industrial Chemicals, Biomonitor, Real-time Monitoring, Biomonitoring Platform A03-161 TITLE: Integrated Architecture for Functional Genomic Measurements TECHNOLOGY AREAS: Biomedical ACQUISITION PROGRAM: DSA, MRMC OBJECTIVE: The overall goal of this SBIR topic is to support efforts in the Objective Force Technology Area: Biomedical. We seek to capitalize upon recent advances in enabling technologies in systems science and functional genomics. DESCRIPTION: Specifically, we seek the development of an innovative, fully-functional, locally-controlled, web-enabled product for integrated analysis of De Novo and Affymetrix datasets. Innovative enhancements of informatic tools for microarray technology supports DoD’s Defense Technology Area Plan in Infectious Diseases of Military Importance, more specifically, STOs III.ME.1996.01 Multi-Stage, Multi-Antigen Plasmodium falciparum Malarial Vaccine; III.ME.1996.02 Drug to Treat Multi-Drug Resistant and Severe and Complicated Malaria; III.ME.2000 a Multi-Antigen Multi-Stage Plasmodium vivax Malaria Vaccine; WRAIR-1D-03 Antimalarial Drug Discovery . BACKGROUND: A critical component of the genomics revolution is the capacity to transform enormous amounts of biological information into a relevant format that readily leads to rapid information-based approaches to biological problems. Advanced integrated analysis methods for modeling, conceptualization and inference of underlying functional relationships within the large-scale datasets are critical if we are to recognize the full potential of the genomics revolution. Currently, functional genomic technologies have outpaced the scientific community’s ability to extract biologically meaningful information. Development of a robust, innovative, flexible web-enabled system to determine causal relationships among genes and proteins – who is regulating whom and how - is imperative as no commercial product currently exists. Specifically, we seek development of an innovative, highly flexible relational product and interface package that will utilize recent advances in areas such as systems science, self-organizing processes, bioinformatic methods, and/or adaptive cooperative computing to develop an integrated architecture for higher level analysis of microarray data sets from both De Novo spotted and Affymetrix technologies while remaining compatible with existing formats and technologies. We seek modeling, simulation and/or analysis tools that will aid in overcoming present difficulties in establishing/identifying core regulatory biological networks/interactions among sets of co-expressed genes within these data sets. Capacity to export output to cross-query community databases (e.g. KEGG, PathDB, TRANSFAC, WIT, SPAD) such that biological significance/relevance can be more easily and fully realized is imperative. The product design must be sufficiently flexible to interface and/or recognize output of existing imaging and analysis packages to include, but certainly is not limited to, Spot, GenePixPro, ImaGene, Partek Pro, Expressionist, etc. This product can be modular, a stand-alone program, add-in for a web browser, or simply integrated with a web browser. The product must serve multiple users at 5 sites, with at least 10 persons accessing simultaneously, yet include provision for scalability to 250 persons with up to 25 simultaneous logins. If interested in responding, applicants are encouraged to contact topic author. PHASE I: Development of a proof-of-concept proposal that will be completed in early Phase II. PHASE II: Develop proof-of-concept beta version of product with at least 60% of desired features. Demonstration of the beta version of the prototype with at least 60% desired features will result in the termination of Phase II. PHASE III Dual Use Applications: The development of a platform for robust analysis of the underlying functional relationships implicit in microarray datasets for DOD drug development/discovery and vaccinology programs would be expected to be readily exploited by researchers in other disciplines. A platform that allows researchers to model and conceptualize data to establish/identify core regulatory biological interactions/functions among sets of co-expressed genes would be expected to advance efforts in vaccine discovery, drug development and discovery, toxicology, and diagnosis and monitoring of infectious diseases of military and civilian import (HIV-1, malaria, pathogenic bacteria, viruses, and biothreat agents). REFERENCES: 1. Zweiger G. 1999. Trends Biotech 17:429-436 2. Thorsson, IT, Ranish, JA, Christmas, R, Buhler, J, Eng, kJK, Bumgarner, R, Goodlett, DR, Aebersold, R., L Hood. 2001 Science 292: 929-934. 3. Halfon, MS, AM Michelson. 2002 Physiol Genomics. 10:131-143. KEYWORDS: microarrays, proteomics, systems biology, adaptive computing, biological systems theory A03-162 TITLE: Haptics-Optional Surgical Training System (HOSTS) TECHNOLOGY AREAS: Biomedical ACQUISITION PROGRAM: DSA, MRMC OBJECTIVE: To develop and demonstrate a computer based Haptics-Optional Surgical Training System (HOSTS) so surgeons can obtain and maintain proficiency in open surgical procedures. The development and commercialization of this technology could potentially provide surgeons with more frequent and higher quality training and lead to improved diagnosis, treatment planning, and procedure rehearsal. This has potential for the Department of Defense (DoD) and the nation to reduce surgical errors, improve patient safety, reduce cost, and improve access to care in fixed medical treatment facilities and improve medical educational training programs both for military and civilian health care providers. DESCRIPTION: Over the past three years, the U.S. Army's Telemedicine and Advanced Technology Research Center (TATRC) has developed a research portfolio in Medical Modeling and Simulation (MM&S) and, as one of several funding sources, has authored SBIR and STTR topics seeking creative, innovative solutions to improve the training of health care providers "from the foxhole to the operating room and beyond". This could improve treatment and reduce surgical errors at fixed military facilities, civilian facilities, medical educational training institutions, and forward deployed locations. Research has fallen into four categories of simulation: (1) PC-based interactive multimedia, (2) digitally enhanced mannequins that are stand-alone or integrated with other systems, (3) virtual workbench (part-task) trainers, and (4) total immersion virtual reality (TIVR). In seeking to support the development of enabling technologies for TIVR, research is being done in many areas, e.g., real-time in vivo tissue properties measurement, tissue-tool interactions, graphics and visualization, learning systems, metrics development and learning transfer assessment, and open architecture strategies. Much discussion and research has focused on the level of visual and tactile realism necessary to effectively transfer skills learned via simulation to actual practice. While tactile feedback devices are desirable to "feel" tissue-tool interactions in minimally invasive (or minimal access) surgery, also desirable may be a system that simulates the "look & feel" of open surgical procedures. While technology is moving TIVR toward reality, we seek creative and innovative solutions to surgical training that are not as reliant on high fidelity haptics feedback. Many surgeons use robotic devices to assist surgery, but some provide little or no tactile feedback. Yet the image visualization is superior, so many surgeons compensate for the lack of "feel". If true when using a robotics device during an actual procedure, perhaps this is at least partially true for a simulated procedure. Traditional techniques for teaching trauma procedures have depended on both the availability of trauma patients and proctors with developed -- and retained -- skills to teach trauma procedures. Other approaches include practice on animals, although animal models of injury often do not reflect human trauma and raise ethical and economic issues related to procuring and maintaining animals for training. Also, practice limited to animals and humans limits the opportunity for trainees -- even trainers -- to repeat and rehearse parts of the procedure that may prove challenging. This open-ended concept requires creative, innovative development so a trainee can learn and practice open-handed surgery procedures on a system that simulates its look and feel. Progress is evident in 3D visualization with or without computer screens. Progress in sensored gloves has been made, and creative innovative virtual environments integrating gloves and viewing devices, e.g., various types of glasses, Head Mounted Display, may allow a surgeon trainee to see and feel a simulated environment. PHASE I: Develop a concept plan for a Haptics-Optional Surgical Training System (HOSTS). The concept should be broad enough so open-handed surgery procedures can be "practiced": a. With or without the presence of tactile feedback, b. Without human, animal, or cadaver tissue, c. With or without Head Mounted Display units that, if present, are equal or lighter weight and equally or less intrusive than those used during the actual procedure, d. Based on embedded metrics for comparison of outcomes, e. With realistic "look and feel" of tissue deformation in response to manipulation of tissue, f. With some type of 3D visualization system, g. Based on instructional design and educational content appropriate to the procedure.
1) Discussions at the Advanced Technologies Applied to Combat Casualty Care (ATACCC) Conference, 13 Sep 02, Medical Modeling & Simulation presentation and strategy sessions. 2) Discussions after the Washington Computer Assisted Surgical Society, 17 Sep 02.
A03-163 TITLE: Re-Usable Intraosseous Infusion Device TECHNOLOGY AREAS: Biomedical ACQUISITION PROGRAM: DSA,MRMC OBJECTIVE: To develop a lightweight, portable, rugged, yet re-usable intraosseous infusion device, that can be used by medics in the field under extreme environmental conditions, for infusion of fluids and drugs via the bone marrow. Although infusion into a specific site is not specified, based on military need, the sternum may be the preferred site. DESCRIPTION: Austere far-forward battlefield environments present numerous obstacles in providing adequate medical care to the injured soldier. In addition to logistic constraints that limit the volume of isotonic crystalloid fluids available to resuscitate the injured soldier, hypotension, environmental and tactical conditions, and/or the presence of mass casualties can combine to lead to excessive delays in obtaining vascular access (1). Intraosseous infusion has been shown to be a rapid, reliable method of achieving vascular access under emergency conditions in children. However, only recently has the concept of intraosseous infusions in adult medical emergencies been revived (1-4). Current intraosseous devices are single use and bulky enough to limit the number of devices that can be carried in the field. Development of a portable device with a reusable handle and disposable intraosseous needles could enable the medic to treat more patients under various combat conditions. PHASE I: This phase should result in a proof of concept workable device, or at the minimum, specifications and mockups of a potentially workable device. The device could conceivably have a lightweight, portable (battery-operated), rugged handle and driver to which are fit sterile, disposable intraosseous needles suitable for infusions into the bone marrow. Because of the incidence of extremity trauma in recent military conflicts (5), the sternum may be the preferred site of choice for intraosseous infusions. Consequently, the intraosseous needle developed must minimize the risk of injury to underlying vital organs and structures. PHASE II: This phase should result in a device that could be tested under various experimental conditions. This phase should also result in a ruggedized device that can be used under austere far-forward battlefield conditions. This device should be small, durable and if applicable, have sufficient battery power under extremes of temperature and moisture conditions. The laboratory at the US Army Institute of Surgical Research has experimental models of severe shock that potentially could be used to test the device for infusion of drugs and fluids, should a company be interested in such a collaboration. PHASE III COMMERCIALIZATION: This instrument would have immediate battlefield application, as well as civilian pre-hospital application, where it could be used by paramedics in the field or on ambulances in both adults and children, under conditions where obtaining vascular access is delayed or conventional catheterization fails. REFERENCES: 1) Dubick M. A., Holcomb J. B. A review of intraosseous vascular access: Current status and military applications. Milit Med 165:552-559. 2) Dubick M. A., Kramer G. C. Hypertonic saline dextran (HSD) and intraosseous vascular access for the treatment of hemorrhagic hypotension in the far-forward combat arena. Annals Acad Med Singapore 26:64-69,1997. 3) Dubick M. A., Pfeiffer J. W., Clifford C. B., Runyon D. E., Kramer G. C. Comparison of intraosseous and intravenous delivery of hypertonic saline/dextran (HSD) in anesthetized, euvolemic pigs, Ann Emerg Med 21:498-503, 1992. 4) Greaves I., Evans G. A., Boyle A. A. Intraosseous infusions in the adult. Trauma 1:291-299, 1999. 5) Islinger R. B., Kuklo T. R. A review of orthopedic injuries in three recent US military conflicts. Milit Med 165: 463-465, 2000. KEYWORDS: Severe hypotension, Resuscitation, Intraosseous, Infusion sites, Vascular access A03-164 TITLE: Diagnostic Microarray Test Based on Comparative Studies of Gene Expression in Humans with Common Inflammatory and Infectious Diseases TECHNOLOGY AREAS: Chemical/Bio Defense ACQUISITION PROGRAM: DSA, MRMC DESCRIPTION:The elucidation of the genetic events underlying the initiation and progression of human diseases is a very critical step in designing better tools for diagnosis and treatment and the advent of high-density microarray technology has opened up a new way of studying the disease process. High-throughput DNA and tissue microarray techniques promise to revolutionize the discovery and validation of novel molecular markers. Detection of exposure to biological threat agents currently uses culture methods, immunoassay and gene amplification and these methods constantly are being perfected for greater sensitivity However, recent events have demonstrated that assessing exposure to a biological threat agent well in advance of onset of illness or at various stages post-exposure would be an important capability to have among the diagnostic options. Patterns of host cell transcription may prove to be useful for diagnosing infection at a very early stage, sometimes within 1 to a few hours post-exposure. The ability of diagnostic assays to identify infected individuals during the prodromal period is essential for successful treatment or intervention following exposure and infection with many disease-causing agents. The identification of early markers of infection using gene profiles by microarray technology offers great promise for revolutionizing disease diagnosis. cDNA microarray technology is a very sensitive method that allows one to analyze thousands of genes simultaneously. On a glass slide thousands of gene fragments are spotted by a robot, RNA samples are then labeled with fluorescent dyes and hybridized to these spots and measured for their level of expression by the intensity of the signal. Various software packages are utilized to generate the ultimate gene list that is significantly altered upon exposure to the test agent. The ultimate goal of this research effort is to derive a series of gene expression responses to biological threat agents to be used as diagnostic markers for exposure as well as to analyze the information to design stage-specific therapeutic regimens. We at Division of Pathology, WRAIR, have been using various molecular techniques to detect early gene responses specific to each biological warfare agent (Das et. al, 1998; Ionin et. al, 1999). The goal was to determine a pattern of gene expression changes in response to each BW agent and to use that pattern to identify the course of impending illness (Mendis et al, 1998). By using microarray technology we have identified a panel of host genes that are up-regulated or down-regulated in response to various BW agents such as Anthrax, plague, Brucella, VEE, Cholera toxin, Botulinum and 2 shock inducing toxins staphylococcal enterotoxin B (SEB) and lipopolysaccharide (LPS). We have also used this gene profile for infection with dengue virus 2. The objective of this topic is to verify the specificity of gene expression profiles obtained for host responses to biological warfare agents after comparing it with common inflammatory diseases to develop a reliable diagnostic assay. Inflammation is the first physiological response induced in the host upon biological warfare agent exposure. Therefore our hypothesis is that some of the genes that we characterized as uniquely altered in biological warfare agent exposure may be also altered in some of the more common inflammatory diseases. In order to develop a robust diagnostic assay using these gene profiles as markers we need to be sure that the genes that are turned on in the host by biothreat agents are not affected by common illnesses. Our group at WRAIR have identified genes that will for example differentiate influenza from anthrax. We have also identified genes that are never expressed in the control untreated samples, however they are altered upon exposure to these various biological threat agents. These genes expression profiles can be measured early in the disease process and used as a diagnostic tool for detection of exposure to such agents. It is therfore important to understand and analyse host responses to common inflammatory diseases to create a unique and reliable diagnostic assay for our biodefense program. This is a high risk research effort and not a mere procurement. The outcome of this research effort will be a better diagnostic assay for detection of biothreat exposure and may be detection of various common illnesses as well. Development of simpler procedures for rapid diagnosis of exposure to these biological threat agents through the detection of host gene responses have broad range of applications in other areas of military and civilian concern. Development of such robust assays will have a great impact not only on civilian readiness to combat bioterrorism but also provide a tool to treat other infectious diseases and detect exposure to toxic agents in the environment. This technology can therefore be considered for the dual use science and technology (DUST) and the dual use applications program (DUAP). PHASE I: The goal is to identify human response genes for a common inflammatory disease. For Phase I the company will perform research to obtain information on how the body's immune cells respond when they have a common inflammatory illness. These responses can be measured by looking at the gene changes in a global way, which means not just measuring gene changes for one or two genes but measuring gene changes for 100-1000 genes at a time. The gene changes can be measured by various techniques available today for high throughput screening of gene expression profile from patients affected with a common inflammatory disease. These assays should be highly reproducible, sensitive and robust for measuring these gene expression changes. Proof of concept can be determined by developing an assay to identify a panel of genes (100-1000) altered for one inflammatory disease compared to control non diseased samples, the results should be statistically significant and they should be reproducible. PHASE II: The assay developed in Phase 1 will be used for analyzing gene changes from multiple patient samples with common inflammatory illnesses. Expand the type of illness studied from one to many such common inflammatory diseases. Gene profiles determined for each of these inflammatory disease will be incorporated into a database. Upon obtaining and analyzing the results from collaborators compare them with our panel of genes identified from biothreat agents. This will enable us to make sure the genes identified to be altered by inflammatory diseases are different from the panel of genes identified for BW agents. These genes will be ultimately used for a diagnostic chip to detect exposure to biothreat agents. Exit criteria will be to successfully demonstrate the expected changes in gene expression profiles specific for that common disease by screening blinded samples. Put these selected genes on a platform for development of a rapid diagnostic assay. Adapt this assay for other biological threat agents and common diseases. PHASE III DUAL USE APPLICATIONS: The information obtained from the measurement of changes in gene expression profile will be of great help in designing better diagnostic assays. This assay will not be restricted to exposure of biological agents but will be applicable to any infectious or common illnesses. The information obtained from these studies will be used to design a diagnostic chip for rapid detection of common inflammatory illnesses and exposure to biological threat agents. This type of a rapid and sensitive diagnostic tool is much needed in today's world and will be of great value commercially to both the defense and civilian community. REFERENCES: 1) Das, R., Mendis, C., Yan, Z., Neill, R., Boyle, T. and Jett, M. (1998) Alterations in Gene Expression show unique patterns in response to toxic agents. In Proceeding of the 21st Army Science Conference, F-P9. 2) Ionin, B., Foley, J., Lee, D., Das, R., and Jett, M. (1999). Differential gene expression pattern induced by staphylococcal enterotoxin B in human kidney cells. Abstract #443. FASEB Journal 13:A1407. 3) Mendis, C., Das, R., Yang, D., and Jett, M., (1998) Identification of alterations in gene expression in response to Staphylococcal enterotoxin B (SEB) using differential display (DD). In the ASCB 38th Annual Meeting, San Francisco, CA. KEYWORDS: Gene expression profiles, host response genes, microarray, inflammatory diseases, rapid diagnostic tests. A03-165 TITLE: Accelerated Drug Design Through Computational Biology TECHNOLOGY AREAS: Biomedical ACQUISITION PROGRAM: DSA, MRMC OBJECTIVE: The objective of this SBIR topic is to enhance rational, structure-based drug design efforts by exploiting the novel technology emerging from the bioinformatics field. We seek lead compound identification through the use of computational models, specifically considering candidate proteins from the malaria-causing parasite Plasmodium falciparum currently being studied. Identification and optimization of lead candidates for antimalarial drug discovery supports the DoD?s Biomedical Technology Area program in Infectious Diseases of Military Importance. 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