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Title: Characterizing virulence-associated small RNAs of Brucella abortus
Significance: Brucella spp. are bacteria that naturally infect a variety of domesticated and wild animals leading to abortions and sterility. These bacteria are also capable of causing debilitating human infections, which often result from human exposure to infected animals and animal products. Importantly, Brucella infections are only rarely fatal in humans, but in these cases of lethal brucellosis, the principal cause of death is endocarditis. Currently, there is no safe and effective vaccine to protect humans against infection with Brucella. During the course of an infection, the Brucella reside within immune cells called macrophages where they replicate in a specialized compartment. The ability of Brucella to survive and replicate within macrophages is essential to their ability to cause disease. One of the ways in which Brucella survive in macrophages is by using two small regulatory RNAs (sRNAs), called AbcR1 and AbcR2. Mutation of the abcR1 and abcR2 genes leads to attenuation of Brucella abortus in macrophages and a murine model of chronic infection. While it is known that the AbcR sRNAs are important in the infection process of Brucella, it is not fully understood how these sRNAs function at the molecular level. The objective of this proposal is to define the novel genetic regulatory elements of the AbcR sRNAs in Brucella spp. In turn, these elements may be targeted in new therapeutic strategies to combat Brucella infections, or to develop a human vaccine against brucellosis. Overall, the proposed work with will aid in the elimination of chronic brucellosis and, thus, advance the development of means in which to eradicate Brucella endocarditis.
PI: Clayton Caswell
Total Award: $397,974
Duration of Award: 1/2015-12/2018
Funding Agency: American Heart Association
Title: Molecular mechanisms regulating collateral formation and remodeling after ischemic stroke
Significance: Cerebrovascular disease of the central nervous system remains a leading cause of death in the US. Neural injury, as a result embolic stroke, is often dictated by the extent of collateral vessels which re-route blood flow (i.e. nutrients and oxygen) to ischemic tissue. Although extensive collateralization in animal models of ischemia has been shown to mitigate neurovascular damage, the mechanism(s) regulating collateral development and injury-induced repair are largely unknown. Using a genetic approach, our studies will establish a new role for a family of axon growth and guidance molecules, called Eph receptors as negative regulators of collateral formation and remodeling. Overall, this investigation will also add some exciting progress in basic and translational vascular research. Our long-term goal is to identify effective, safe, and feasible drug targets that enhance collaterogenesis and translate them into clinical applications for occlusive vascular disease.
PI: Michelle Theus
Total Award: $308,000
Duration of Award: 4 years
Funding Agency: American Heart Association
Title: Mechanism of Hepatitis E Virus Replication and Pathogenesis
Significance: Hepatitis E virus (HEV) is an important but extremely understudied human pathogen causing significant public health problem in developing countries but is also endemic in the United States and other industrialized countries. In this project, we will identify the genetic determinant(s) for HEV cross-species infection and host range, and delineate the role of host immune factors in HEV infection and host anti-HEV defense. The information from this project will be important for devising effective prevention and treatment strategies against HEV.
Total Award: $1,585,850
Duration of Award: 7/2013 to 6/2017
Funding Agency: NIH, NIAID
Title: The relationship between human and livestock microbiome, enteric pathogens and diarrhea
Significance: The overall goal is to define the microbiomes of humans and animals, and to determine their interdependence in two rural agro-ecosystems. The intent is to use this information to optimize human nutrition, improve maternal and children health, and thereby support the sustainability of livestock in Nepal and Uganda.
Most enteric pathogens in humans have animal origins. Where humans and domesticated animals live in proximity enteric pathogens can be shared; these can remain subclinical or can result in disease in either host. This dynamic relationship is particularly amenable to study in isolated rural settings to study how changes in the gut microbiome in humans affect that of their animals, and vice versa, and to record the functional significance of these changes. Infants are especially sensitive to changes in environmental microbes because their immune systems and gut microbiota are still developing, and therefore more sensitive to pathogens. We propose a comparative study to determine the interdependence of mother and her infant with that of livestock in rural household in Nepal and Uganda. Comparative analysis will identify the prevalence of infectious disease, climate change on their distribution and identify influencing key factors to reduce the disease burden. Conversely, constant exposure to livestock microbiota may protect humans from inflammatory diseases that are independent of infection. We also propose to investigate any influence of microbial composition by the human genetic variation that controls expression of the glycosylation of gastrointestinal mucosa.
The objective is to generate human and livestock microbiome data from distinct ecological region of Nepal and Uganda during both the rainy and dry seasons, and to measure the zoonotic disease burden. This study will lay the groundwork for developing nutritional and dietary strategies to reduce enteric disease of children and livestock.
Total Award: $400,000
Direct: $348,498/2 years
Indirect: $51,502/2 years
Duration of Award: 8/2013 to 7/2015
Funding Agency: USAID
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.
Total Award: $397,974
Indirect: $142, 974
Duration of Award: 3/2013 to 2/2016
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.
Total Award: $1,970,992
Duration of Award: 1/2013 to 12/2017
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
Duration of Award: 6/2012 to 4/2014
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.
Total Award: $66,226
Duration of Award: 24 months
Funding Agency: AKC Canine Health Foundation
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.
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
Duration of Award: 5/2010-4/2015