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Research Awards

Title: MicroRNA expression in the NZB/W lupus mouse

Significance: This grant will identify if there are alterations in microRNA in specific cells and in urine as mice develop systemic lupus erythamatosus. This can lead to the identification of new biomarkers that may be predictive of disease and the development of new therapeutics to treat disease.

PI: Christopher M. Reilly
CO-PI's: Rujuan Dai, Ansar Ahmed, David Caudell

Total Award: $397,974
    Direct: $255,000
    Indirect: $142, 974

Duration of Award: 3/1/2013 to 2/29/2016

Funding Agency: NIH; National Institute of Arthritis and Musculoskeletal and Skin Diseases

Title: A chicken model to study hepatitis E virus pathogenesis

Significance: Hepatitis E is an important public health disease with a high mortality rate of up to 28% in infected pregnant women. Recently, chronic hepatitis E virus (HEV) infection has become an emerging and significant clinical problem worldwide in immunocompromised individuals such as organ transplant recipients and patients with HIV, lymphoma and leukemia with considerable morbidity and mortality. The long-term goal of this project is to delineate the predictive immunological factors leading to the progression into chronicity and to understand the mechanisms of HEV immunopathogenesis. The results will be important for devising effective prevention and treatment strategies against HEV.

PI: X.J. Meng
CO-I's: Tanya LeRoith, F. William Pierson, Lijuan Yuan

Total Award: $1,970,992
    Direct: $1,250,000
    Indirect: $720,992

Duration of Award: 1/1/2013 to 12/31/2017

Funding Agency: NIH; NIAID

Title: Dietary Rice Bran Supplementation for Gut Mucosal Immunity and Rice Crop Improvement

Significance: Rice Bran is a globally accessible, underutilized food ingredient with distinct stoichiometry of phytochemicals and prebiotics for induction of non-specific gut mucosal immune responses. This agricultural byproduct represents a promising and practical dietary based solution for increasing innate resistance against enteric pathogens (i.e. rotaviruses and Salmonella) that cause diarrhea worldwide, with high mortality and disease burden in developing countries. In collaboration with Dr. Elizabeth Ryan (PI) at Colorado State University, for this contract project Dr. Yuan's research team will determine whether selected rice bran can reduce the susceptibility to infection and diarrhea upon virulent human rotavirus infection in gnotobiotic pigs, examine the ability of rice bran to promote the development of mucosal and systemic T and B cell immune responses and improve the protective efficacy of oral rotavirus vaccine, and evaluate the prebiotic effect of rice bran on the growth of probiotic Lactobacillus rhamnosus GG and modulation of the gut microbiota.

Subcontract PI: Lijuan Yuan

Total Subcontract Award: $399,999
    Direct: $363,636
    Indirect: $36,363

Duration of Award: 6/15/2012 to 4/30/2014

Sponsor: Bill and Melinda Gates Foundation

Title: Longitudinal Study Investigating the Progression and Pathogenesis of Atypical Hyperadrenocorticism in Scottish Terriers

Significance: Increased serum alkaline phosphatase (ALP) activity is common in Scottish Terriers. Findings in our preliminary work indicate that this increased ALP activity is attributable to hyperadrenocorticism (HAC). HAC is a chronic debilitating disorder in dogs and contributes to the development of negative health and behavior outcomes including diabetes mellitus, obesity, musculoskeletal weakness, immune system dysfunction, and inappropriate urination. However, what is unclear is why these affected Scottish Terriers demonstrate laboratory evidence of HAC at an early age and why it appears to be driven by a less common mechanism than seen in other breeds. We propose to examine this disorder from three different perspectives, using traditional laboratory, functional, and genetic tests. These efforts will help us understanding why Scottish Terriers are predisposed to developing atypical HAC and how best to treat and screen for this disorder.

PI: Kurt Zimmerman
CO-PI: David Panciera
CO-I: W. Edward Monroe
CO-I: Reid Tyson
CO-I: Tanya LeRoith
CO-I: Ina Hoeschele

Total Award: $66,226

Duration of Award: 24 months

Funding Agency: AKC Canine Health Foundation

Title: Role of The Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) Nucleocapsid Protein PxxPxxP SH3 Signaling Motifs in PRRS Pathogenesis

Significance: Porcine reproductive and respiratory syndrome virus (PRRSV) infection is arguably the most economically-important disease of the global swine industry. The recent emergence of the "pig high fever diseases" caused by PRRSV in China and Vietnam with high mortality and significant economical losses exemplifies the need for continued research on this important swine pathogen. The long-term goal of the project is to determine whether PRRSV N protein affects the host cellular signaling pathways leading to disease progression and persistent infection. The proposed studies will help our understanding of the mechanism of PRRSV pathogenesis and help devise effective prevention and control strategies in the future.

PI: Scott P. Kenney
CO-PI: X.J. Meng

Total Award: $130,000

Duration of Award: 8/15/2011 to 8/14/2013

Funding Agency: U.S. Department of Agriculture - NIFA

Title: Development of a DNA-based nanoscale optical fiber biosensor assay to detect Brucella infections in elk and other wildlife

Significance: Brucellosis is a devastating disease that affects humans and a variety of animals throughout the world, including much of Europe, Central and South America, Africa, Asia, the Middle East, and even the Arctic. The last remaining reservoir for Brucella abortus in the United States is in the wild bison and elk in the Greater Yellowstone Area (GYA). Brucellosis eradication in cattle within the US has been a multi-billion dollar, multi-decade project that has yielded considerable success. However, in the last few years the disease has spilled over from affected wildlife to cattle populations in the states surrounding the GYA, thus threatening anew continued success of the US' national Brucellosis Eradication Program. Presently, the changes in the disease transmission dynamics, between and among domestic livestock and wild ungulate reservoirs of Brucella species (especially in elk and bison), underlying this increased incidence and prevalence of cases are poorly understood. Consequently, the expert community has joined together to call for both large- and small-scale initiatives aimed at supporting research and development in several specific areas determined to constitute critical scientific and technological gaps and needs.

Our overall goal is to develop a highly sensitive and mobile detection device that will accurately and quickly detect the presence of Brucella species DNA in a variety of samples. Our hypothesis is that nanoparticle-based optical fiber biosensors (NOFS) will prove to be superior biomedical assays that can be applied to the diagnosis of Brucella nomenspecies in wildlife in the GYA. To accomplish this goal our specific aims are to: (i) Develop a NOFS assay to detect specific regions of Brucella DNA, and (ii) Multiplex the NOFS assay to enable DNA regions specific to B. abortus or non-B. abortus nomenspecies to be detected and differentiated simultaneously.

PI: Thomas J. Inzana
CO-I: Randy Heflin
CO-I: Abey Bandara

Total Award: $200,000

Duration of Award: 3 years

Title: Novel vaccine against Norovirus

Significance: Noroviruses are an important cause of acute gastroenteritis, affecting people of all ages, in both developed and developing countries. In this study, we will develop a vaccine against noroviruses based on norovirus subviral particle, the P particle. This project will be conducted by a research team with multidiscipline experts in molecular virology, immunology, and vaccine development at the Cincinnati Children's Hospital Medical Center (CCHMC) with Dr. Xi Jiang as PI, and the Virginia Polytechnic Institute and State University (Virginia Tech) and the LigoCyte Pharmaceuticals Inc as subcontractors. In the subcontract at Virginia Tech, we will first conduct natural history studies of human noroviruses in gnotobiotic pigs to establish the gnotobiotic pig model of human norovirus infection and disease. We will then characterize the safety, immunogenicity and broadness of the candidate P particle vaccines in protection against various noroviruses using the gnotobiotic pig challenge model. Our studies will lead to the next level of evaluation by the Phase I human clinical trials and future commercialization of the vaccine.

Subcontract PI: Lijuan Yuan

Total Subcontract Award: $1,348,162
    Direct: $875,000
    Indirect: $473,162

Duration of Award: 5/15/2010-4/30/2015

Title: Evaluation of the immunogenicity and cross protection of Lanzhou trivalent reassortant rotavirus vaccine

Significance: Rotavirus gastroenteritis is responsible for ~35,000 deaths of infants and young children per year in China. An effective vaccine is needed to protect against rotavirus disease and death. A trivalent rotavirus reassortant (human x lamb) vaccine has been developed by Lanzhou Institute of Biological Products and completed the phase II clinical trial in China. This vaccine also provides an opportunity to dissect the homotypic and heterotypic immune responses induced by the vaccine and the efficacy of cross-protection against G1 rotavirus challenge in the gnotobiotic pig model. The specific aim of the project is (1) to determine the immunogenicity and cross protective efficacy of the live oral trivalent vaccine (G2, G3, G4, P[12]) and LLR vaccine (G10P[12]) in the gnotobiotic pig model of human rotavirus (G1P1A[8]) infection and disease, with and without the lactobacilli adjuvants; (2) to identify the mechanism of cross protective immunity induced by rotavirus vaccines. This information will facilitate the design of more effective rotavirus vaccines.

PI: Lijuan Yuan

Total Award: $200,000
    Direct: $126,104
    Indirect: $73,896

Duration of Award: 6/1/2010-11/30/2011

Title: USDA/APHIS/VS Terminology Support

Signficance: The Nation’s public health and food supply is at constant risk from accidental or malicious introduction of exotic animal diseases. In 2002, Congress recognized the severity of these threats and provided funding to USDA to enhance early detection of foreign animal disease agents and newly emerging diseases and to better respond to animal health emergencies (including bioterrorist events) that threaten the Nation’s food supply and public health. The National Animal Health Laboratory Network (NAHLN) was formed to coordinate Federal laboratory capacity with the extensive infrastructure (facilities, professional expertise, and support) of State supported laboratories. The National Veterinary Services Laboratory (NVSL) serves as the National Reference Laboratory for the NAHLN and provides training, test procedures, proficiency testing, assay controls, and equipment while the laboratories of the NAHLN provide the laboratory space and personnel necessary to ensure that the U.S. has the capacity and capability to detect and respond to an animal disease outbreak.

The NAHLN concept is dependent on timely sharing and analysis of laboratory data. The concept that has been adopted by NAHLN to allow data sharing is based on adherence to standards and development of the ability to timely message in a specified Health Level 7 (HL7) format. The incorporation of the NAHLN dependent standards, especially as the first several messages are developed, can be challenging for a NAHLN laboratory both from a technical and terminology standpoint. Most LIMS require mapping current Lab terminology to the standardized NAHLN terminology external to the LIMS system and then developing a process to message the mapped data. Some laboratories need assistance in developing an IT process for extracting data, mapping to consistent terminology and subsequent messaging. Laboratories may also need terminology assistance to assure that their data is translated correctly according to the defined standards.

Terminology needs are dynamic. The terminology referenced as well as the data requirements for the NAHLN-related messages need to be updated and documented as new disease programs and/or diagnostic tests are incorporated into the NAHLN. Each new disease program has the potential to introduce new diagnostic tests, new specimen types, new species concerns, etc. The terminology needs must be reviewed and updated to accommodate these additions. Currently, defined message formats exist primarily for the NAHLN result message, additional formats are being developed for the NAHLN order message, referral message and update messages. These new formats will require a review of terminology needs and creation of appropriate terminology subsets for use in messaging. In addition, standardized terminology is very dynamic with concepts being retired or revised regularly. As the terminology adapts and changes, NAHLN laboratories need to be aware of these changes so their messages can conform to the updates on the NALHN database. This cooperative agreement will enhance terminology automation, maintain terminology alignment with enhancements to NAHLN functionality and the addition of new content and new content areas.

PI: Jeff R. Wilcke
CO-I: Julie Green

Total Award: $300,000
    Direct: $272,728
    Indirect: $27,272

Duration of Award: 1 year

Title: FDA Veterinary Medical Terminology

Signficance: The Structured Product Label (SPL) initiative offers a number of advantages versus traditional paper labels including: 1) The drug product label can be associated with electronic medical records systems giving unprecedented access to label information at the point of medical care; 2) the ability to include, in a single XML document, information from all parts of the drug label information (including sound files and movie files); 3) users can reference a known up-to-date version of the label maintained at a central (web) location; and 4) it is possible to streamline label regulation, particularly as concerns validating a label against FDA style standards and business rules.

Adoption of the Structured Product Label initiative by the FDA Center for Veterinary Medicine (FDACVM) presents a number of significant challenges. The SPL was developed and adopted without significant input from veterinary professionals. Although human and veterinary pharmaceutical labels have much in common, terminologies selected as standards for human labels may lack necessary veterinary content. It can also be said that various label sections (e.g., Food Safety Warning Section) are simply not represented by sections defined for human labels. FDACVM’s Office of New Animal Drug Evaluation (ONADE) and Office of Surveillance and Compliance (OSC) are each responsible for animal pharmaceutical labels, but their perspectives are different. ONADE sees and evaluates labels as they are being developed. OSC sees and evaluates labels as part of their interaction with the end users of veterinary pharmaceuticals. During their normal regulatory activities ONADE will encounter new indications and new animal classes OSC will encounter new adverse drug effects and drug interactions.

The most significant challenge for FDACVM is the transition from current systems designed to regulate paper labels to those that support evaluation and maintenance of labels rendered in SPL. One of the major changes will be the expanded use of external (to FDA) terminology standards necessary for creation of valid (based on FDA’s own guidelines) SPL-based labels. It seems clear that FDACVM will require significant modification of its label management infrastructure. FDACVM must either adapt existing systems or develop new ones. In either case, it will be important to manage internal and external terminologies as part of any adequate regulation of SPL-based labels.

The Veterinary Terminology Services Laboratory’s (VTSL) approach to this project will begin with a comprehensive assessment of existing ONADE and OSC information management systems and internal terminologies. Internal terminologies will be compared to terminology standards necessary for SPL compliance. Once the review is completed, alternate terminology management strategies will be developed so that the impact on FDACVM systems development can be assessed. VTSL will also provide training for key FDA personnel in the various information technologies employed in the SPL.

PI: Jeff R. Wilcke
CO-I: Suzanne Santamaria

Total Award: $131,241
    Direct: $82,802
    Indirect: $48,439

Duration of Award: 1 year

Title: Nanoscale Optical Fiber Biosensor Assays for Detection of Category A and B Select Agents

Significance: The threat of an intentional release of bacterial select agents prompts the need for their rapid, culture-free diagnosis that can be conducted in the field or in laboratories with only basic diagnostic capabilities. Optical fiber biosensors are attractive devices that can detect, record, and transmit information regarding a physiological change or the presence of various biological and chemical materials in the environment. These devices can be easily operated by non-specialist personnel and do not require high vacuum, high temperature, organic solvents, or clean-room facilities. Our overall goal is to develop sensitive, specific, and rapid nanoscale optical fiber biosensors for the diagnosis of the Category A and B select agents Francisella tularensis, Burkholderia mallei, and B. pseudomallei, as proof of principal that these tests can be applicable to a wide variety of other agents. Our hypothesis is that specific antigenic epitopes or regions of the DNA of these bacteria can be targeted for use in rapid, specific, and sensitive diagnostic assays. To accomplish our goal our specific aims are to: (i) develop a DNA-hybridization assay using nanoscale optical fiber biosensors coupled to DNA probes to detect specific oligonucleotide sequences; (ii) develop an antigen-binding assay using nanoscale optical fiber biosensors coupled to antibodies to detect specific antigens; and (iii) enhance the sensitivity and optimize the specificity of the nanoscale optical fiber biosensors in detecting oligonucleotide sequences and antigens specific to infectious bacteria. In addition, we will use Real-Time PCR and latex agglutination assays as control assays to compare the sensitivity and specificity of DNA-based or antigen-based optical fiber biosensor assays. The novel bioengineered optical fiber assay is rugged, portable, and inexpensive when compared to competing technologies such as surface plasmon resonance. These sensors will fill an important void that exists in the rapid diagnosis of Category A and B select agents, but can be broadly applicable and to the diagnosis of a variety of biological agents.

PI: Thomas J Inzana
CO-I: James R Heflin
CO-I: Abey Bandara

Total Award: $375,604
    Direct: $250,000
    Indirect: $125,604

Duration of Award: Two years

Title: Mechanisms of Immune Modulation by Probiotics

Significance: Rotavirus gastroenteritis poses a tremendous ongoing disease burden in the US and worldwide, with costs to health care and society exceeding one billion dollars annually in the US and even more immense morbidity and mortality in developing countries. Four years of funding (R01) from National Center for Complementary and Alternative Medicine (NCCAM), NIH are awarded to Dr. Lijuan Yuan and her team to determine if the use of probiotics can enhance vaccine efficacy in gnotobiotic pig models of human rotavirus infection and to identify the underlying mechanisms by which probiotics exert the adjuvant effects. Identifying a novel function of probiotics next to their role as direct regulators of disease is highly significant and innovative. This knowledge will facilitate the clinical uses of probiotic adjuvants for vaccines against rotavirus and other enteric virus-induced diseases, which could have a real impact on global health by augmenting vaccine efficacy at a relatively moderate cost.

PI: Lijuan Yuan
CO-I: Stephen Boyle, Marlice Vonck

Total Award: $1,560,523
    Direct: $1,000,000
    Indirect: $560,523

Duration of Award: 08/01/09-07/31/2013

Title: USDA,APHIS,VS Centers for Epidemiology and Animal Health

Significance: This agreement will expand the work begun by the Veterinary Medical Informatics Lab (VMIL) in standardization of terminology for the USDA’s National Animal Health Laboratory Network, broadening the scope to include the USDA, APHIS, Veterinary Services standards for taxonomy. The work will specifically focus on updating and improving the taxonomy and breed standards published in the Surveillance and Data Standards for USDA/APHIS/Veterinary Services, used by all USDA animal programs. Improved standardization will enhance surveillance and response to emerging animal diseases in the US, including avian influenza and with bio-terrorism potential.

PI: Jeff Wilcke
CO-I: Julie Green

Total Award: $65,000
    Direct: $59,101
    Indirect: $5,909

Duration of Award: 09/02/08-09/01/09

Title: Identifying PRRSV structural components that activate regulatory T cells and diminish protective immunity

Significance: This research project will address an important question in Porcine Reproductive and Respiratory Syndrome virus (PRRSV) immunology by determining and characterizing which components of the virus stimulate regulatory T cells (Tregs), resulting in diminished protective immunity. A major obstacle in stimulating protective immunity against PRRSV is the ability of the virus to modulate and dampen the immune response, leading to virus persistence. This immune modulation not only allows PRRSV to replicate and cause disease, but it also leads to severe secondary respiratory infections as well. One way the virus is able to do this is by activating regulatory T cells. Regulatory T cells not only dampen the immune response to the antigen that activated them, but they also non-specifically dampen the immune response to other antigens as well. Determining which viral components are necessary for regulatory T cell activation will be vital in designing future effective vaccines that avoid this arm of the immune response.

PI: Tanya LeRoith
CO-I: XJ Meng, Kevin Pelzer

Total Award: $59,249
    Direct: $59,249

Duration of Award: 1 year, starts November 1, 2008

Funding Agency: National Pork Board

Title: Understanding the Immunopathogenesis of Porcine Multisystemic Wasting Syndrome: the Immunological Effects of PCV2 and PRRSV Co-infection

Significance: Porcine circovirus associated diseases (PCVAD), including PMWS, are widespread in the pork industry in the United States. Additionally, the incidence of more severe PMWS has been increasing. Although PCV2 has been recognized as the major contributor to PCVAD, it is difficult to reproduce the disease with PCV2 alone. Typically infection by other viruses including PRRSV is required for clinical disease. However, the contribution each virus makes to the manifestation of clinical disease is unknown, but is presumed to be a result of immune modulation by the viruses. This research will attempt to identify the contribution of each virus in enhancing disease. Understanding the effects of each virus on the immune system and how they interact is vital for vaccine development and for instituting other control measures.

PI: Tanya LeRoith
CO-I: XJ Meng, Kevin Pelzer

Total Award: $60,669
    Direct: $60,669

Duration of Award: 1 year

Funding Agency: National Pork Board

Title: Attempt transmit hepatitis E virus to goats

Significance: The objective of this study is to attempt to transmit hepatitis E virus to goats, and to establish a goat animal model for the study of human hepatitis E.

PI: XJ Meng
CO-I: D. Phillip Sponenberg

Total Award: $24,866
    Direct: $15,688
    Indirect: $9,178

Duration of Award: 6 months

Funding Agency: NIAID, NIH

Title: Fullerenes Counteracting Organophosphorus Threats

Significance: Organophosphorus (OP) compounds are potent, volatile chemical agents that have been used as agents of terrorism (e.g., their use against the Kurds in Iraq in the 1980s and their release in Japan in 1994 and 1995). The OP nerve agents are chemically similar to OP insecticides and exert their acutely toxic biological effects by inhibiting acetylcholinesterase (AChE) enzyme in the nervous system. Although treatments are currently available for rescue from OP-induced cholinergic poisoning that follows AChE inhibition, they have a limited spectrum of effectiveness. Solubilized carbon-containing ‘buckyballs’ (C60 and C80 fullerenes) supplied by Luna Innovations, Inc., Blacksburg, have properties that provide potential to contribute to counteract severe OP-induced toxicity. The water solubility of these fullerenes will allow them to be easily administered and distributed in the body; properties associated with their carbon cages will allow them to enter cells to exert antidotal action. They are safe, have capability to interact with and inactivate OP compounds, and could counteract OP-induced oxidative stress associated with the severe toxicity that can occur following exposure to nerve agents. The work to be done will examine the effectiveness of C60 and C80 fullerenes to inactivate OP compounds in vitro and effectively antidote OP toxicity in vivo.

PI: Marion Ehrich
CO-I: Bernard S. Jortner; Luna Innovations, Inc. (Roger Van Tassell, Chris Kepley)

Total Award: $946,432 (includes annual subcontracts to Luna Innovations, Inc.)
    Direct: ~$674,435 total
    Indirect: ~$217,728 total

Duration of Award: ~ 3 years; 9/4/08 – 5/31/11

Funding Agency: NIH

Title: A chicken model to study HEV pathogenesis

Significance: The lack of a practical animal model for HEV is a major obstacle for understanding the mechanism of HEV pathogenesis. This project will utilize a novel chicken model system to understand the pathogenesis of HEV, and the data from this project will help devise preventive and control strategies against HEV.

PI: X.J. Meng
CO-I: F.W. Pierson, T. LeRoith, Y.W. Huang

Total Award: $1,266,300
    Direct: $800,000
    Indirect: $466,300

Duration of Award: 03/01/2008 to 02/30/2012

Funding Agency: NIAID, NIH

Title: Mechanism of hepatitis E virus replication and pathogenesis

Significance: The lack of knowledge on HEV biology and pathogenesis has greatly hindered the development of a vaccine against HEV. This project will delineate the structural and functional relationship of HEV genes using reverse genetics and animal models, and the results will aid in the development of a live-attenuated vaccine against this important but extremely understudied human pathogen.

PI: X.J. Meng
CO-I: P.G. Halbur, Y.W. Huang

Total Award: $1,561,797
    Direct: $1,000,000
    Indirect: $561,797

Duration of Award: 03/01/2008 to 02/30/2012

Funding Agency: NIAID, NIH