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


Building Sustainable Human and Institutional Capacity for HIV Care
PI: King K. Holmes, Wm. H. Foege Chair of the Dept. of Global Health, and director, Center for AIDS and STD
Sponsor: Health Resources and Services Administration (HRSA), $13,456,710

The International AIDS Education and Training Center (IAETC) project grant was first awarded to the University of Washington (UW) by the US Health Resources and Services Administration (HRSA) in 2002, and reflects a cooperative agreement between HRSA; UW; and the University of California, San Francisco (UCSF), UW’s long-time technical partner. The International Training and Education Center for Health (ITECH), implements the IAETC. I-TECH carries out PEPFAR-supported activities in 15 countries and the Caribbean region with the help of 60 organizational partners, including ministries of health, health training institutions, and local non-governmental organizations. With its partners, I-TECH works toward the PEPFAR five-year goal of achieving sustainable, high quality, comprehensive HIV primary care for people living with HIV and AIDS in resource-limited countries. The organization brings to PEPFAR and Global Health Initiative (GHI) target countries the technical expertise of its universities, HRSA’s broad experience implementing Ryan White Care Act programs in the United States, and lessons learned and best practices gleaned from experience working in the United States.

I-TECH activities are designed to support the six building blocks associated with the WHO Health Systems model: service delivery; health workforce development; health information systems; medical products, vaccines, and technologies; health systems financing; and leadership and governance. I-TECH is guided by the following strategic objectives:

• Provide technical assistance to governments; central, district, and provincial health departments; pre-service training institutions; and other stakeholders to prepare and retain a qualified workforce and build strong and responsive national health care delivery systems;

• Assist host countries to assess need and design customized programming that aligns with national strategic plans for HIV and AIDS and Partnership Frameworks with the US government;

• Work with local partners to transition sustainable activities, programs, and other assets to regional ownership while building their capacity to attract and manage diversified sources of funding; and

• Serve as a knowledge portal and dissemination mechanism for key information on HIV and AIDS.

I-TECH activities contribute to the achievement of PEPFAR targets for HIV care, treatment, and prevention by strengthening human capacity to deliver health care services and by strengthening the institutions and health systems in which those health care services are situated. I-TECH ensures that it is meeting goals and objectives through: 1) robust program monitoring at the network level and in each country program, consistent with PEPFAR programmatic categories; 2) a continuous quality improvement framework that provides ongoing assessment of program success in meeting goals and objectives; 3) an internal performance management system that includes performance standards and work plan implementation monitoring; and 4) program evaluations that demonstrate effectiveness.

Institute of Translational Health Sciences (ITHS)
PI: Mary 'Nora' Disis, professor, medicine; associate dean, Translational Health Sciences
Sponsor: National Center for Research Resources (NCRR) $9,832,606

We propose to create the Institute of Translational Health Sciences (ITHS) to support the increasingly interdisciplinary and collaborative nature of translational research. The ITHS will significantly enhance collaboration between three major research institutions --the University of Washington (UW), Fred Hutchinson Cancer Research Center, and Children’s Hospital and Regional Medical Center -- and strengthen research ties with the Benaroya Research Institute, Group Health Cooperative, and existing clinical and research infrastructure across the 5-state WWAMI region. Finally, the ITHS will provide a common infrastructure for a rich pool of translational research resources and create solid pathways of communication and research-based interactions with the community.

The ITHS will function as a "collaboratory"; a structure that spans all institutions to foster collaboration, career development, education, and the translational research process itself. Overarching goals include: (1) enhancing and further developing collaboration networks within our environment and into the community, (2) providing education and career development at all levels, (3) fostering innovative research, research infrastructure and the integration of innovative technologies into translational research, and, (4) creating a community that prioritizes translational research. The ITHS will adapt resources to support the members' evolving research needs. To achieve such flexibility we will use a dynamic evaluation process with frequent assessment of resources and activity followed by adjustment of short term goals so that more rapid impact can be made toward the long term goal of maximizing support for innovative translational research within and across partner institutions and the community.

Tenofovir and Emtricitabine/tenofovir Chemoprophylaxis to Prevent HIV Acquisition
PI: Connie L. Celum, professor, global health and medicine; director, UW International Clinical Research Center
Sponsor: Bill and Melinda Gates Foundation, $9,734,062

The University of Washington proposes a proof-of-concept trial among HIV-negative partners in HIV discordant couples in Africa to assess the safety and effectiveness of pre-exposure prophylaxis (PrEP) with tenofovir (TDF, Viread™) and emtricitabine/tenofovir (FTC/TDF, Truvada™) versus placebo on HIV acquisition. Our hypothesis is that PrEP will reduce the rate of HIV acquisition by 60% compared to placebo. The trial has 90% power to detect >30% effectiveness of pooled endpoints in the two PrEP arms and 83% power to detect >30% effectiveness of each active arm compared to placebo. The discordant couples design enables evaluation of effectiveness of PrEP by gender and level of exposure (i.e., frequency of sexual activity, and CD4 and HIV viral load in the HIV-infected partner). The co-primary endpoint is to assess safety and adverse events rates in the PrEP arms versus the placebo arm. Secondary endpoints by study arm include 1) viral resistance and viral set-point in seroconverters, 2) drug adherence, and 3) risk behavior reported by both partners. Archived blood and genital samples will enable study of virologic and immunogenetic correlates of HIV transmission. HIV discordant couples are an important population to study for the safety and effectiveness of PrEP, as the majority of transmissions in Africa occur among HIV discordant couples, who will thus be a priority group for use of PrEP if it is found to be safe and effective in reducing HIV acquisition.

Disease Control Priorities Network
PI: Christopher J. Murray, professor, global health; director, Institute for Health Metrics and Evaluation

Sponsor: Bill and Melinda Gates Foundation, $7,184,488

International and national decision-makers need access to valid, reliable, and comparable information on the costs and consequences of policy alternatives for population health. The Disease Control Priorities Network (DCPN) project aims to improve the allocation of health resources across a wide range of investment options, including interventions, service delivery platforms, and research and development of new health technologies. Within the overall goal, there are four project objectives: (1) inform allocation of resources across interventions and health service delivery platforms; (2) inform allocation of resources to scientific discovery and product development; (3) create a Disease Control Priorities Network (DCPN), comprising institutions in many countries; and (4) core analytics, methods, and management. These objective will be the focus of the proposed DCPN project.

A Program for Cell-Based Diabetes Therapy
PI: Michael Schwartz, professor, medicine; director, Diabetes & Obesity Center of Excellence
Sponsor: Washington State Life Sciences Discovery Fund Authority (LSDFA), $3,994,222

Diabetes occurs when the capacity to secrete insulin can no longer meet the body's needs. This, in turn, results in elevated blood glucose levels that over time, can cause devastating impairment of the retina, peripheral nerves, kidney and heart that collectively constitute a leading cause of morbidity and mortality in Washington State. Whereas Type 1 diabetes is an autoimmune disease that occurs most often in children and adolescents, type 2 diabetes is more common in adults, particularly those with obesity, a major diabetes risk factor. In association with the growing problem of obesity, the prevalence of diabetes has doubled over the past decade in both the US and Washington State and, while treatments for diabetes exist, neither is curable. In 2007, the UW Medicine Diabetes and Obesity Center of Excellence (DOCE) was created an housed in 32,000 square feet of research space in the new biomedical research campus at South Lake Union (SLU). Through a multi-institutional collaborative effort we have recently created the Diabetes-Stem Cell Program (DSCP) whose overarching goal is to unite expertise in stem cell biology with that in developmental biology of pancreatic beta cells, basic and clinical aspects of diabetes, implantation biology, and immunology in a joint scientific endeavor. Key objectives of the DSCP include not only the creation and commercialization of a new, cell-based method for diabetes treatment, but also the development of strategies to eliminate the risk of tumor formation in cell implants, and to optimize methods for cell differentiation and metabolic analysis. Research space, administrative support and other resources at SLU have been committed this program, and we recently recruited two faculty that sit at the interface of diabetes and stem cell biology to provide scientific leadership for this new program. We have now united them with a 10 other highly skilled faculty from the DOCE, ISCRM, UWMC, Benaroya Research Institute, and the VA Puget Sound Health Care System to launch this new program, whose goal is to translate basic research findings into a new and potentially curative approach to diabetes treatment.

Fluctuation Reduction with Insulin and GLP-1 added together
PI: Jeffrey Probstfield, professor, medicine 
Sponsor: Sanofi-Aventis U.S., $3,854,031

In order to conduct the proposed randomized, controlled, multicenter, open-label study investigator-initiated FLAT-SUGAR trial, the primary funding is supported by Sanofi-Aventis US with donations of other medications and devices by several other companies. The Sponsor-Investigator is the University of Washington, The Data Center is the University of Texas at Houston School of Public Health and there are 12 clinical sites with expertise in CGM to enroll and follow 130 participants for 8 weeks of run-in and an active treatment period of 26 weeks.

Parent-Child Assistance Program
PI: Therese M. Grant, associate professor, psychiatry and behavioral sciences; director, Fetal Alcohol and Drug Unit
Sponsor: Washington State Department of Social and Health Services, $2,930,328

The Division of Alcohol and Substance Abuse of DSHS has contracted for the continuation of a training/ replication model of the Parent-Child Assistance Program (PCAP). UW PCAP will maintain the Seattle and Tacoma PCAP sites, with the administrative offices located at the Fetal Alcohol and Drug Unit of the UW Dept. of Psychiatry. UW PCAP will continue to provide comprehensive and ongoing training and program evaluation for the PCAP ten-site program: in King,Pierce,Yakima,Grant,Spokane,Spokane Tribe,Cowlitz, Clallam, Kitsap and Skagit counties. PCAP sites provide direct advocacy services to the highest risk mother abusing alcohol and/or drugs during pregnancy, and their families. Comprehensive and ongoing training and program evaluation will be provided to all centers to ensure replication of essential advocacy model principles and to monitor process and outcomes.

HVTN Core Travel Budget 2011-2012
PI: Janine Maenza, clinical assistant professor, medicine
Sponsor: Fred Hutchinson Cancer Research Center (FHCRC), $2,810,052

The subcontractor will provide both the contract fares and the administrative support to handle the travel and conference/meeting needs for faculty and staff of the HIV Vaccine Trials Network (HVTN), as well as HIV/AIDS Network Coordination (HANC)-related travel and conferences.


The subcontractor shall: 1.) Provide the cost savings regarding travel fares and 2.) Provide support to coordinate travel, meetings, and conferences

A Comprehensive catalog of human DNasel hypersensitive sites
PI: John Stamatoyannoupoulos, associate professor, genome sciences
Sponsor: National Human Genome Research Institute (NHGRI), $2,615,448

The overall aim of this proposal is to establish a comprehensive, high-quality catalog of human DNasel hypersensitive sites (DHSs) spanning all major tissue lineages. We plan to map DNasel hypersensitive sites a physiological resolution across the genome with high sensitivity and specificity. The major focus of our production effort will be on data quality; a strategy that serves the Human Genome Project well. Accordingly, samples will be rigorously screened in a pipeline fashion, with only a select set advancing to whole-genome data collection. To ensure the broadest possible coverage of both unique and non-unique genomic territories, a synergistic combination of three technologies (DNasel-array, digital mapping of DNasel cleave site sequences, and Quantitative Chromatin Profiling) will be applied. This combination will enable mapping of >95% of the DHSs in the genome of each cell type. Independent validation provides the ultimate quality standard. We therefore plan to validate the DHS independent catalogue in a statistically rigorous fashion using hypersensitive Southerns, a well-established, gold-standard assay. Since DNasel hypersensitive sites are generic markers of a broad spectrum of human cis-regulatory sequences, the utility of the catalog will be greatly enhanced by the classification of DHSs into major functional categories including promoters, distal elements (enhancers, LCRs), and insulators. Validation of DHS functional classes will be accomplished using well-tested cell and transgenic assays of biological function. 

Comprehensive Biology: Exploiting the Yeast Genome
PI: Trisha Nell Davis, professor, biochemistry 
Sponsor: National Institues of Health (NIH), $2,565,863

Since its inception the Yeast Resource Center has specialized in extracting information about protein function from genome sequence. We began when the first eukaryotic genome was completed (budding yeast) and developed an array of technologies to decipher protein function from genome sequence. In this application, we make the natural progression towards understanding how protein variation affects protein levels, modification, function and structure. In our first core, we propose to develop technologies to identify different protein variants or isoforms. In our second core we develop methods to quantify proteins by mass spectrometry with a focus on determining absolute levels of a proteins. In our third core we develop technologies to study how protein variation affects protein function. Finally we develop technologies to determine the structures of proteins complexes not amenable to high-resolution methods such as x-ray crystallography and NMR.

Immunological and Virological Events in Early HIV Infection
PI: James Mullins, professor, microbiology
Sponsor: W.M. Keck Foundation, $2,502,001

The overriding goals of this competing renewal application are to understand the interactions between host immunity and viral replication, evolution and fitness, during and beyond acute HIV-1 infection. Our work is targeted to the goals of enhancing control and prevention of infection. The first 5 years of support for this work have been very productive, yielding important insight into early infection host-pathogen dynamics, the impact on viral fitness that occurs as a result of immune escape, the dynamics and cellular site of virus in HIV-1 exposed individuals that remain seronegative, therapeutic interventions, and the use of this data in the formulation of state-of-the-art vaccine immunogen designs. Our program is unique in that we focus on indepth, multifaceted analysis of subjects that were enrolled while in acute HIV-1 B infection and then followed longitudinally for many years. Our additional foci on donor-recipient partner pairs and viral fitness represent state of the art leadership in these areas. In this renewal, we have added a new Project and the new dimension of evaluation of initially HIV-discordant couples and subsequent heterosexual transmission involving HIV-1 subtypes A, C and D. Our studies are critically important to the continuation of our growing understanding of primary HIV infection and to the design of protective HIV vaccines. State-of-the-art immunological, genetic and virologic technologies will be brought to bear to further dissect the biological mechanisms underlying host control, in four highly interactive research projects. Our Program is composed of three Projects that combine the areas of viral evolution and adaptation to host immunogenetics and cellular immune responses. We also have four Cores, covering the essential elements of Administration, Clinical, Virological and Repository, and Biostatistics functions.

Stem Cells and Cardiovascular Repair
PI: Charles E. Murry, professor, pathology, bioengineering, medicine
Sponsor: National Institutes of Health (NIH), $2,490,839

This program descended from our 52 year-old P01 grant (HL03172), retired due to successive budgetary cuts, to form this translational program focused on myocardial infarct repair using adult and pluripotent human stem cells, with an emphasis on pre-clinical translation. There are 3 projects and 3 cores. Project 1 (Murry, Schwartz, Mahoney) begins by studying synergies in formation of new myocardium and vasculature by combining clinically relevant sources of human cardiomyocytes, endothelium and MSCs. Next, they utilize a recently identified human cardiovascular progenitor from ESCs, capable of generating cardiomyocyte endothelium and smooth muscle, to generate vascularized myocardium in the infarct. Finally, these investigators explore the mechanisms through which grafts induce a collateral arterial supply from the host coronaries. Project 2 (Laflamme, Santana) studies the cellular electrophysiology of human cardiomyocytes, beginning with a genetic selection system to generate pacemaker vs. working-type human myocytes. Next these investigators will identify the signaling pathways that specify hESC-derived cardiomyocytes into working-type vs. pacemaker phenotypes, with a goal of determining whether the pacemaker cells are precursors of the working-type cells or a separate stable branch. Lastly, they use cell transplantation to assess the ability of the different myocyte subtypes to couple with host cardiomyocytes and test their differential effects on electrical stability. Project 3 (Torok-Storb, Bowen-Pope) develops a pre-clinical model in the dog for cardiac repair. They begin by developing a system for scalable production of cardiomyocytes from their recently generated canine induced pluripotent stem cells (iPSCs). Next, they investigate if MSCs can promote repair by endogenous cells and exogenous cardiomyocytes, including testing if MSCs induce third-party tolerance to allogeneic cardiomyocytes. Finally, they perform transplantation studies with canine iPSC-derived cardiomyocytes and MSCs, creating a clinically relevant model of cardiac stem cell therapy in the dog. These projects are supported by a Stem Cell Core (A) that trains investigators in hESC use and provides differentiated cells such as cardiomyocytes; an Outcomes Core (B) that provides histology services and a central source of expertise in animal models (mouse, rat, dog) of myocardial infarction, cell transplantation and physiological assessment; and an Administrative Core (C) that coordinates meetings and seminar series, provides fiscal support and plans the annual PPG retreat.

Regional AIDS Education and Training Centers Program
PI: David H. Spach, professor, medicine 
Sponsor: Health Resources and Services Administration (HRSA), $2,337,960

Goal: The overarching goal is to improve access to health care, the quality of health care, and health outcomes for all persons, especially minority persons, living with HIV/AIDS by developing/sustaining culturally sensitive HIV clinical care expertise in WAMIO communities.

 Overview of Program Plan: Case finding is promoted by increasing awareness of HIV in rural and minority communities, and motivationally encouraging and educationally supporting all primary care clinicians to integrate HIV testing into routine medical care. It addresses unmet need and improving access to health care in communities by increasing the number of clinical care providers willing and able to provide HIV/AIDS clinical care and treatment. The plan supports improving health outcomes and the quality of health care by training/educating clinical care providers on Department of Health and Human Services treatment guidelines, and provides longitudinal education/training and other forms of treatment decision support across each State. Different methods of training are employed to accommodate different learning styles. Trainings are culturally appropriate and consistent with adult learning theory.

UW Autism Center of Excellence 
PI: Bryan King, professor and vice chair, psychiatry and behavioral sciences
National Institute of Child Health and Human Development (NICHD), $2,157,213

Autism spectrum disorder (ASD) is a developmental disorder once believed to be a rare disorder, it is now recognized that ASD afflicts approximately 1 in 166 persons. Approximately one million individuals are affected in the U.S. with an annual cost of $90 billion which primarily reflects school age and adult services. Preventive efforts aimed at reducing autism symptoms and associated behavioral challenges could result tremendous cost-savings to society and improve the lives of individuals suffering from autism and their families. The UW ACE will pursue the following goals and objectives: (1) Identification of early risk indices for autism. As an extension of our earlier work, we seek to discover early risk indices for autism that can be detected in infants, including genetic/familial, brain structural/chemical, neurophysiological, and behavioral indices, that can increase our ability to identify infants who will eventually develop autism or autism-related symptoms. (2) Development of effective intervention methods for infants and toddlers. We plan to conduct two studies examining the efficacy of novel early interventions for infants and toddlers with autism or autism-related symptoms. (3) Understanding variation in outcome and adaptation in autism. In addition to the intervention studies, we seek to continue to follow a sample of 70 children with ASD and their families who have been comprehensively evaluated at ages 3, 6, and 9 years. We will study the relation between individual differences in early brain development and variation in course and symptom severity in adolescents with autism and their families.

RIG-I-Like Receptors and Novel Innate Immune Pathways for Adjuvant Discovery and Development 
PI: Michael J. Gale, professor, immunology
National Institutes of Health (NIH), $2,149,625

The Research Project is designed to identify, characterize, and deliver immune adjuvants and novel innate immune factors for preclinical and clinical evaluation within therapeutic strategies aimed controlling RNA virus infections. The unique focus of our Program is our overall approach to identify adjuvant compounds that i) activate the RIG-I-like Receptor (RLR) pathways, and ii) that can mitigate viral strategies of RLR pathway suppression by pathogenic RNA viruses. In addition, iii) our studies will identify novel innate immune factors and their pathway that function to enhance immunity and offer therapeutic potential as possible targets for the control of RNA virus infection.



















Provided by the Office of Research and Graduate Education, UW School of Medicine, Oct. 5, 2011