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Quarterly Report of Top Awards
UW School of Medicine
Based on award amounts received between January 2011 and March 2011


NWRCE for Biodefense and Emerging Infectious Diseases Research
PI: Samuel I. Miller, professor, medicine, microbiology, genome sciences and immunology
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID), $7,355,616

The Region X Northwest Research Center of Excellence (NWRCE) in Biodefense and Emerging Infectious Diseases is an essential component in a nationwide network of biomedical research programs to combat infectious disease threats to the population. The NWRCE is an established interactive center studying Gram-negative bacterial pathogenesis, innate immune responses to Gram-negative bacteria, and product development for Gram-negative bacterial pathogens. Region X possesses unique strengths in biotechnology platforms, including genomics, proteomics, and bioinformatics. The NWRCE is currently a highly interactive and thematic program focused on Gram-negative bacterial pathogens. Within that general consistent focus, which has existed since its inception, are three themes: (1) mechanisms of Gram-negative bacterial pathogenesis, (2) innate immune responses to Gram-negative bacterial pathogens (3) Therapeutic development to prevent or treat Gram-negative bacterial diseases. The NWRCE is centered at the University of Washington (UW) in Seattle, with multiple sites in Seattle, two in Oregon, and 1 in Idaho. The projects, cores, and sites are highly interactive and have worked together for many years. The majority of added investigators to this new application to continue and expand funding for the NWRCE have had long collaborative relationships with members of the center. The interactive nature and focus of the NWRCE is a major strength of the program and allows the NWRCE to rapidly and nimbly respond to national priorities to achieve important objectives with respect to Gram-negative bacterial infections.

Institute for Simulation and Interprofessional Studies (ISIS) - Optional Phase II
PI: Brian K. Ross, professor, anesthesiology
Sponsor: U.S. Army Medical Research and Materiel Command (USAMRMC), $3,504,000

This grant is broken down into 3 projects: 1) Distributed Skills Training and Healthcare Delivery; 2) Individual Healthcare Trianing; and 3) Team Training with Continuity of Care (TTCC). In project 1, we will develop an interactive online consortium toolkit including a staffing model tool, assessment/evaluation tool associated with curriculum and outcomes measures, scenarios development tool, and preparation of human subjects documents tool. In project 2, we will develop and validate curriculum for the Chest Procedures pilot program and validate training efficacy of 8 pilot programs including Wound Closure, Cardiac Respiratory Exam, Ultrasound, Central Venous Catheter, Suprapubic Catheter Insertion, Laparo-endoscopic skills, and development of a Intelligent Virtual Cadaver. In project 3, we will vadiate training efficacy of team training and develop the Medical Emergency Black Box system (MEBBIS).

Towards Development of a Field-Deployable Imaging Device for TBI
PI: Pierre Mourad, associate professor, neurological surgery 
Sponsor: U.S. Department of Defense (DOD), $2,602,379

IEDs produce head injuries in 40% to 62% of surviving soldiers. These head injuries include extensive edema and contusions (a mix of edema and small-scale hemorrhage), intracranial bleeding, and traumatic axonal injury (TAI). Most brain-injured soldiers do not, however, receive adequate brain imaging studies until they are flown to rear-echelon medical service centers such as in Germany. This is because MRI is unavailable in or near the theatre of war (and contraindicated in a significant percentage of patients because of the presenceof metal fragments) and because of the paucity of operational CT machines at medical centers in Iraq. In the mean time, due to the lack of adequate neuro-imaging, acute neurosurgical care in response to closed TBI often requires a complete hemicraniectomy simply to assay the extent and location of injured brain. There exists, therefore, a critical need for robust brain-imaging systems at and near the battlefield. An additional critical need is a system capable of sensing any clinically relevant changes in brain subjected to mild TBI such as subtle changes to white matter. This is relevant, for example, for assessing the battle readiness (e.g., ‘vulnerability’) of soldiers. These gaps in patient care reduce the quality of care and potentially, therefore the quality of life of injured soldiers. This gap also defines a critical need for rugged, field-deployable systems capable of imaging the presence and extent of cerebral edema and hemorrhage as well as injury to white matter.

Mitochondrial Antioxidants, Aging and Healthspan
PI: Peter S. Rabinovitch, professor, pathology
Sponsor: National Institutes of Health (NIH), $1,894,689

This application for renewal of our longstanding Program Project is based on a highly focused, integrated and interactive effort to examine the hypothesis that mitochondrial antioxidants are capable of resisting agerelated disease and improving health and function in multiple organ systems in mammals. This builds on past progress, including observations that mice overexpressing mitochondrially targeted catalase have extended lifespan, improved cardiac, and muscle health and resistance to epithelial cancers. We therefore have developed an increasing focus on health and healthspan, including study of acute models of decline in organ function that can serve as surrogate assays for similar disorders in aging. In this Program Project we propose four Projects to apply this approach to disorders of aging in which mitochondrial reactive oxygen species (ROS) and ROS induced damage play an important role: 1) Cardiac health and protection from heart disease and failure; 2) Muscle health and protection from antiretroviral drug induced sarcopenia; 3)Protection from epithelial cancers; 4) Protection from neurodegenerative disease. The Projects are supported by four Cores: 1) Administrative; 2) Mouse pathobiology; 3) Proteomics; and 4) Mitochondrial Protective Chemistry. In each of these Projects and Cores we seek to understand the mechanisms underlying the role of mitochondrial ROS in aging and health. Each of the Projects is also pursuing a highly translational goal of establishing the ability of mitochondrial protective drugs to deliver similar benefits to sustained physiologic function and healthspan.

Department of Defense HIV/AIDS Care and Treatment Program
PI: Ann E. Downer, executive director, International Training and Education Center for Health (I-TECH)
Sponsor: U.S. Department of Defense, $1,785,000

Military personnel are at high risk for HIV infection, and it is incumbent on the part of national governments to develop programs that educate soldiers on the prevention of HIV and AIDS and that provide care and treatment for those soldiers who are HIV-positive. The United States Department of Defense (US DOD), in collaboration with partners has already made prevention services available to its soldiers in the Namibian Defense Force (NDF) and its staff at the Ministry of Defense (MOD). In 2006, the US DOD in collaboration with the International Training and Education Center on HIV (I-TECH) began a program seeking to ensure that all Ministry of Defense/Namibian Defense Force personnel have access to quality HIV and AIDS care and treatment, and to also establish adequate linkages between care and treatment and the existing prevention services at MOD/NDF sites. This proposal is for continuation and expansion of the project. I-TECH under the leadership of the U.S. DOD is currently assisting the Namibia MOD/NDF to finalize its draft sectoral HIV/AIDS Policy. In close collaboration with the US DOD HIV/AIDS Program Office, I-TECH is in the process of establishing care and treatment services within the MOD/NDF health care facilities, including renovation of the designated facilities, training of health care workers and the establishment of adequate monitoring systems. Furthermore, I-TECH is currently working with the Ministry of Health and Social Services (MOHSS) to ensure that the MOD/NDF HIV care and treatment facilities meet the certification requirements of the MoHSS in terms of adequate space, sufficient staff with the proper training in the use and prescribing of antiretroviral therapies, treatment of opportunistic infections associated with HIV disease, adherence counseling and other HIV and AIDS topics, drug procurement and monitoring, provision of laboratory testing, and monitoring and evaluation. I-TECH is also coordinating with US DOD to work closely with the U.S. DOD-funded prevention partner to ensure that program linkages between prevention services and care and treatment, and that all HIV-positive soldiers have access to (or receive) ‘prevention with positives’ education and counseling.

Male Contraception Research Center Grant
PI: William J. Bremner, Robert G. Petersdorf Professor and Chair, Department of Medicine
Sponsor: National Institute of Child Health and Human Development (NICHD), $1,768,538

World population continues to increase at a frightening rate, particularly in developing countries. Even at the very optimistic projection of 2.5 children per woman, global population will grow to over 15 billion by year 2100. In addition, approximately one-quarter of all pregnancies are unwanted, leading to millions of abortions (1.5 million surgical or medical abortions annually in the United States) and approximately 100,000 deaths worldwide per year of otherwise healthy young women due to the complications of abortion. It is well established that men will use contraceptives (approximately 30% of all contraception in the U.S. now is accomplished with male methods) and there are substantial problems with safety and acceptability of existing female methods. Therefore, the development of new, effective, safe, reversible male contraceptives is an extremely important societal goal.The work undertaken in this application is designed to increase our basic and clinical knowledge of reproductive processes in the male with particular relevance to contraception. Four research projects, a Program for Fellows and New Investigators in Male Contraception, and an Administration Core Unit make up this center grant which incorporates the talents of outstanding investigators of varied backgrounds and professional training into an interactive research program in reproductive biology. We have structured this Center to meld superb science with the practical goal of applying new basic knowledge as quickly as possible to studies in human beings. We hope that, in this way, our work will address critical needs of society. 

Exome Sequencing of Simons Simplex Collection Trios
PI: Evan E. Eichler, professor, genome sciences 
Sponsor: The Simons Foundation, $1,665,398

We propose to complete whole exome sequencing on 400 trios from the Simons Simplex Collection (SSC), focusing on the comprehensive detection of sequence and structural variation. Given the ascertainment and phenotyping strategy employed in the creation of the SSC, particular emphasis will be placed on the identification and confirmation of de novo mutations. If funded, and based on current throughput, we will complete sequencing within 4 months of being provided 10μg of DNA per sample. Pre-publication data release will take place after no more than 3 months for data cleaning, validation and analysis. Moreover, this data release will include a suite of visualization and annotation tools for the broader scientific community. Our investigator group includes Evan Eichler and Jay Shendure at University of Washington, Matthew State at Yale and Dan Geschwind at UCLA. Together these laboratories share deep interests and records of accomplishment in gene discovery in Autism Spectrum Disorders (ASD); proven abilities in high-throughput whole exome sequencing; and complementary expertise in the areas of bioinformatics and pathway analyses, structural variation detection, rare variant association approaches, analysis of gene expression and function, and the clinical care of affected individuals and their families.

Action to Control Cardiovascular Risk in Diabetes (ACCORD) Follow-up Trial
PI: Jeffrey L. Probstfield, professor, medicine
Wake Forest University, $1,646,264

Treatment and follow-up of the ACCORD participants ended on June 30, 2009. The richness of this population, the documented success of the ACCORD trial, and the unexpected glycemia findings suggest that it would be scientifically worthwhile to follow these participants beyond the scheduled end of treatment/follow-up for at least an additional 5 years (i.e., through about October 2014). It is proposed that the participants continue to be followed more closely for events and key measures of health for an additional period of time. This project will be known as ACCORDION.

PI: Bruder F. Stapleton, chair and professor, pediatrics 
Sponsor: Children's Hosptial and Regional Medical Center, $1,406,512

Salary support funds transfered from Children's Hospital and Regional Medical Center (CHRMC) to the University of Washington for U.W. employees.

Intrabiliary MR/RF-Enhanced Chemotherapy of Malignant Biliary Obstructions
PI: Xiaoming Yang, professor, radiology
Sponsor: National Institutes of Health, $1,122,121

The prognosis of malignant biliary obstructions is very poor due to their low resection rate and low tolerance to chemotherapy and radiotherapy. Although intrabiliary stenting is the current favorable choice for the treatment of malignant biliary obstructions, its high complication occurrences require repeated interventions and longer hospital stay with a high economic burden. In addition, with the current technology, the systemic administration approach does not permit delivery of high-dose chemo-drugs into the target biliary walls, rather it causes high risk of undesired toxicities of other organs.In the present project, we aim to overcome these problems of currently-available approaches (including surgeries) for treatments of malignant biliary obstructions. Based on our previous extensive experiences on a novel intraluminal MR imaging (MRI)/radiofrequency heating (RFH) prototype system, in this project we will establish a completely new interventional technology with two innovative techniques, including (a) intrabiliary MRI-guided local delivery of high-dose chemo-drugs into the CBD walls and their adjacent tissues; and (b) intrabiliary MRI-guided, RFH-enhanced chemotherapy of malignant CBD obstructions. To reach this goal, we propose three Milestones: (i) optimization of the new intrabiliary MRI/RFH prototype system; (ii) preclinical validation of the feasibility of using the new intrabiliary MRI/RFH technology to guide and enhance chemo-drug delivery into the CBD walls and their adjacent tissues; and (iii) translation of this novel technology into clinical practice, to treat the patients with malignant biliary obstructions.We are convinced that the success of this project will open new avenues that could lead to significant breakthroughs in the management of malignant biliary diseases, using MR/RF-interacted interventional oncology. The further expansion of this new technology should benefit the other advance medicines, such as heat-enhanced gene therapy, temperature-sensitive therapies using targeted nanoparticles and peptides, photodynamic therapy, and radiation therapy. These advanced technologies can be further used to effectively manage the obstructive diseases in other systems with luminal structures, such as kidney-ureters, urethra-prostate, and esophageal-stomach-intestines.

Action to Control Cardiovascular Risk in Diabetes (ACCORD) - Follow-On - Central Laboratory
PI: Santica M. Marcovina, research professor, medicine 
Sponsor: Wake Forest University, $1,097,865

This contract will fund a 5-year post-trial follow-up study after termination of study-assigned treatments in the ACCORD trial. The follow-up will determine whether differences seen during the study in mortaility, CVD events, and microvascular diseases persist or change over time and whether other differences emerge. In addition, the follow-up will examine patterns of key clinical variables, including key safety parameters, and their association with clinical events. The Northwest Lipid Metabolism and Diabetes Research Laboratories proposes to continue it's role as the Central Laboratory for this follow-up study.

NHANES Quantiferon Gold Tuberculosis Testing 2011-2015
PI: David Koelle, professor, medicine
Sponsor: Centers for Disease Control and Prevention (CDC), $1,022,937

Iinfection by Mycobacterium tuberculosis (MTB) is a serious health problem. The Centers for Disease Control and Prevention (CDC) is a branch of the US federal government that conducts surveillance for MTB infection. The CDC conducts a long-term study called NHANES that plans to collect blood samples on approximately 16,000 US citizens within the US during 2011-2015. The CDC seeks a contractor to perform a new blood test for MTB infection called Quantiferon Gold In-Tube (QFG-IT). The UW has expertise in performing the QFG-IT test, in MTB infection, and in performing work for the CDC for its' NHANES studies. This proposal is a response to a solicitation from the CDC seeking a contractor to perform these tests.

Virological Analysis of Breakthrough Viruses from the STEP Trial
PI: James I. Mullins, professor, microbiology and medicine 
Sponsor: Fred Hutchinson Cancer Research Center (FHCRC), $1,004,199

We will perform deep-sequencing using either 454/pyrosequencing or SGA at up to 3 time points in the first 10months of infection. A total of 185 samples of plasma and PBMC are targeted for this analysis. We will restrict our analysis to the gag, env and nef regions of the viral genome – gag and nef being the regions of the viralproteome demonstrating an impact due to vaccination in our initial studies, and env corresponding to a controlsequence with no counterpart in the vaccine.All of the real-time PCR quantitation of multiplex amplicons will be performed in the Mullins laboratory. Recentimprovements in the PCR technology worked out in the Mullins lab suggests that only 10% of the earlyspecimens evaluated will have <50 templates available for sequencing. If >50 templates are available,pyrosequencing will be performed, with about 2/3 of the work to be completed in the Mullins lab. The remaining1/3 of the pyrosequencing and the GSA on the samples with <50 copies, will be performed in the MHRP lab.A data analysis pipeline has been worked out by and is being refined in the Mullins lab. This technology, aswell as the laboratory techniques for pyrosequencing will be transferred to the MHRP laboratory over thecoming year.

Implantable Computers to Augment Brain Function
PI: Eberhard Fetz, professor, physiology and biophysics
Sponsor: W.M. Keck Foundation, $1,000,000

The brain is the world’s most powerful autonomous computer, whose operations remain to be understood and whose functions can be rescued when impaired. Current electronic and MEMS technology is poised to create implantable computer systems that interact continuously with the brain. We will develop and deploy autonomous recurrent brain-computer interfaces (R-BCI) that implement novel interactions between brain sites. By operating continuously, the R-BCI will allow the brain to learn to exploit these new resources to optimize its function. This novel paradigm opens many fundamentally new research directions, depending on the site of recording and stimulation, and the programmable transform between recorded activity and stimulation. The R-BCI also has numerous important clinical applications for bridging damaged biological pathways and for strengthening weak neural connections.

Minority Health-GRID Network: A Genomics Resource for Health Disparity Research
PI: Deborah A. Nickerson, professor, genome sciences
Sponsor: Morehouse University, $996,813

The persistence of health disparities in medically underserved minority communities remains one of the most vexing public health problems facing our nation. Emerging evidence indicates that the etiology of health disparities involves dynamic interactions between genetic, behavioral and social-environmental determinants. Yet the field lacks robust datasets that integrate clinical phenotypes and genetic analysis with ‘real-time’ surveillance of health outcomes in minority patient cohorts. The proposed ‘grand opportunity’ (GO) project is designed to address this void in the field by creating a novel national resource --the Minority Health Genomics and Translational Research BIo-Repository Database Network (Minority Health-GRID Network). The Minority Health-GRID Network will create a biomedical informatics/bio-repository resource that is capable of capturing the multi-dimensional factors that mediate the differences in health outcomes observed in minority communities. From this important resource a set of individuals who are hypertensives and normotensives will undergo whole exome resquencing to elucidate rare variants (and common variants) involved in the etiology of blood pressure and related outcomes e.g. kidney failure and drug resistances. This exome data will supply a rich resource of information on the population genetics of African-Americans which will be used to guide the association analysis. It has been demonstrated that methods used to detect association between complex traits and common variants are underpowered to analyze rare variants. Therefore this data set will be analyzed using the latest methods which have been developed to detect rare variant associations for both qualitative and quantitative complex traits controlling for important confounders such as social-economic status, BMI, etc. Since the study is being carried out in African-Americans, admixture mapping can be used to guide us to regions containing genes where rare variants are involved in the etiology of hypertension. Although admixture mapping is a powerful tool, when carry-out association analysis population admixture/substructure, both local and global, needs to be controlled and is potentially a greater problem for the analysis of rare variant than common variant data. In order to address this important problem current methods used to control for population admixture/substructure (e.g. principal components analysis) will be evaluated for rare variant association studies and new methods will also be developed to tackle this problem.













Provided by the Office of Research and Graduate Education, UW School of Medicine, April 11, 2011