Grant Announcements

Title: Biodegradable Microcapsules Containing Stem Cell Derived-Biological Pacemaker to Treat Mice with Bradycardia

Significance: Cardiovascular disease is one of the most prevalent and chronic illnesses in Virginia. In 2011, ~5.9% (~365,842) of Virginians was diagnosed with cardiovascular diseases, which was responsible for 13,332 deaths in our State (www.vahealth.org). Despite a better understanding of the systemic nature of cardiac arrhythmia and improved application of implantable electronic pacemaker devices, there are significant side effects associated with electronic pacemaker devices and no effective permanent means of treating these diseases. The proposed stem cell-derived beating biological pacemakers in combination with microencapsulation techniques are a highly innovative regenerative medicine strategy for the treatment of cardiac arrhythmias. Successful completion of the proposed study will establish the fundamental basis for stem cell/biomaterial-based personalized regenerative medicine to treat cardiovascular diseases and the approach can be potentially transferred to remedy other types of disorders, such as traumatic brain injury, thus offering enormous therapeutic potential for patients.

PI: Jia-Qiang He
Co-I/Collaborator: Kevin Edgar

Total Award: $199,994

Duration of Award: 7/2016 - 6/2018

Funding Agency: Commonwealth Health Research Board (CHRB)

Title: Effect of maternal immune factors in shaping the infant gut microbiota

Significance: Gut colonization of commensal bacteria decreases the risk of neonatal sepsis. This suggests that dysbiosis of the neonatal gut microbiota may represent a risk factor and contribute to increased incidence of infection in infants. Our ongoing experiments show that host adaptive immune status plays a key role in shaping the gut microbiota. They beg the question, however, of the relative contributions of maternal and de novo immunity sources to the observed microbiota changes. The contribution of maternal-derived immune factors to infant microbiota composition has not been revealed. Lack of such information has prevented identification of specific risk factors in the microbiota. The proposed research aims to improve neonatal health by identifying these risk factors, which in turn will lead to the design of probiotic therapies against neonatal infections and related complications.

PI: Xin Luo

Total Award: $161,000

Duration of Award: 4/2016 - 3/2018

Funding Agency: NIH NIAID

Title: Mechanisms Regulating Cerebral Arteriogenesis and Neurorestoration        

Significance: Traumatic brain injury (TBI) is the most common acquired central nervous system (CNS) injury in the U.S, afflicting over 1.7 million Americans annually. Due to a paucity of safe and effective therapies, survivors are left with persistent motor and cognitive deficits that substantially reduce their quality of life. Mechanical damage to the cerebrovascular circulation creates an ischemic milieu, which exacerbates neural tissue loss. Therapies designed for neuroprotection and repair have underscored the importance of vascular health and remodeling in the trauma microenvironment. Interestingly, therapeutic arteriogenesis has become an important target for the prevention and treatment of peripheral tissue ischemia, however, limited information exists regarding its effects on neural preservation and recovery of function within the CNS. The overarching goal of our research is to provide important mechanistic insight into the pathophysiological relevance of cerebral arteriogenesis following TBI. Specifically, the current study will employ a novel cell-specific, transgenic murine approach to investigate the central role of Eph signaling in suppressing arteriogenesis. Unraveling the molecular mechanism(s) underlying this important adaptive response and its potential as a therapeutic target for neurorestorative intervention in the brain may reveal novel targets for drug discovery.

PI: Michelle Theus
CO-I: John Chappel, Hehuang Xie

Total Award: $1,730,277

Duration of Award: 4/2016 - 3/2021

Title: Dissecting the Role of the ORF3 Gene of Porcine Epidemic Diarrhea Virus in Viral Pathogenicity       

Significance: Porcine epidemic diarrhea virus (PEDV) first emerged in the United States in 2013, leading to the death of more than 10 million piglets since. The virus has now spread to more than 32 different U.S. states causing immense economic losses to the swine industry. Currently, there is no USDA fully-licensed vaccine in the United States against PEDV, and thus development of an effective vaccine will be critical for the prevention and control of this deadly disease. In this USDA project, we will first dissect the role of ORF3 in PEDV pathogenesis, and then use molecular biology and reverse genetics system to develop a modified live-attenuated PEDV vaccine, and such a vaccine would greatly aid in the control measures of this deadly disease.

PI: Adam J. Rogers
Mentor: X.J. Meng

Total Award: $149,944

Duration of Award: 1/2016 - 1/2018

Funding Agency: USDA NIFA

Title: Characterization of a novel genetic pathway required for Brucella virulence

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. Additionally, Brucella spp. are considered threats as potential biological weapons. Currently, there is no safe and effective vaccine to protect humans against infection with Brucella, and antibiotic treatment against brucellosis is prone to disease relapse. During the course of an infection, the Brucella reside within immune cells called macrophages where they replicate in a specialized compartment, and the ability of Brucella to survive and replicate within macrophages is essential to their ability to cause disease. We have recently discovered that a transcriptional regulator, which we have named VtlR, is required for the ability of the bacteria to survive and replicate within host cells, and moreover, this regulator is essential for chronic Brucella colonization in an animal model of infection.

Preliminary data has led to the hypothesis that VtlR controls the expression of essential genes for Brucella pathogenesis. We have determined that VtlR regulates the expression of a limited subset of three genes putatively encoding small hypothetical proteins. Strikingly, these hypothetical proteins are highly conserved among numerous bacterial species, both pathogenic and beneficial, but there is currently no information regarding the molecular function(s) of these proteins in prokaryotic biology. The objective of this proposal is to define these novel virulence-associated elements in Brucella spp. In turn, these proteins may be targeted in new therapeutic strategies to combat Brucella infections, or to develop a human vaccine against brucellosis. Moreover, these studies will shed light on the role of these novel protein elements in a wide variety of bacteria, and it is possible that these proteins may be exploited as a means of alleviating detrimental infections, as well as enhancing beneficial bacteria-host interactions.

PI: Clayton Caswell

Total Award: $458,638

Duration of Award: 9/2015 - 8/2018

Funding Agency: National Institute of Allergy and Infectious Diseases

Title: CRISPR/Cas9 guided production of genetically engineered pigs lacking CD8+ T cells

Significance: Genetically engineered (GE) pigs can be a great model in biomedical research as pigs are physiologically, anatomically, and immunologically similar to humans. CRISPR/Cas9 system is currently widely used to generate targeted modification of genome in various species. In this project, homology directed repair pathway at high frequency during CRISPR/Cas9 mediated genetic modification will be used to generate GE pigs. The proof of concept study using the CD8+ T cell deficient pigs for elucidating the mechanism of human norovirus vaccine-induced protection will provide insights that can facilitate the development of effective vaccines as norovirus infection is the leading cause of acute viral gastroenteritis in people of all ages in the United States, but mechanisms of vaccine-induced protective immunity have not been identified.

PIs: Lijuan Yuan, Kiho Lee

Total Award: $438,725

Duration of Award: 8/2015 - 5/2017

Sponsor: Office of the Director, National Institutes of Health

Title: Improving molecular-based research skills while investigating and elucidating the biodiversity of parasites in raptors to better understand transmission processes  

Significance: Part of NSF Learning Links: Research experiences for undergraduates in biology to help increase the numbers of under-represented minors in the science fields. STEM students from Johnson C. Smith University will undergo training in molecular, in vivo and in vitro methods to study protozoan parasites that cause encephalitis in many avian species.

PI: Alexa C. Rosypal, Johnson C. Smith University, Charlotte, North Carolina
Mentor/Research Collaborator: David S. Lindsay

Total Award: $194,205

Duration of Award: 8/2015 - 7/2017

Funding Agency: NSF Research Initiation Award

Title: Evaluating NLR Modulation of Canonical and Non-Canonical NF-kB Signaling in IBD

Significance: Crohn's disease and ulcerative colitis are common manifestations of inflammatory bowel disease (IBD). These two debilitating disorders afflict approximately 1.4 million Americans and over 4 million people worldwide. Previous work from our lab has identified a novel sub-group of intracellular proteins that function to negatively regulate inflammation and tumor development during IBD. We have previously shown that one of these proteins, NLRP12, is a potent modulator of experimental colitis and inflammation driven tumorigenesis in pre-clinical mouse models. During IBD, NLRP12 modulates gastrointestinal inflammation through the attenuation of either canonical or non-canonical NF-kB signaling. While the role of the canonical NF-kB signaling pathway during IBD is well established, the contribution of the non-canonical NF-kB cascade is relatively uncharacterized. The overall goal of this proposal is to explore NLRP12 and its modulation of canonical and non-canonical NF-ĸB signaling in IBD in more detail. The evaluation of these unique proteins and pathways represents a novel direction that we hope will ultimately contribute to future discoveries associated with immune system homeostasis in the gut and lead to new therapeutic strategies targeting IBD.

PI: Coy Allen
CO-I: Tom Cecere

Total Award: $161,000

Duration of Award: 7/2015 - 6/2017

Funding Agency: NIH NIDDK

Title: Allosteric Regulation of a Viral RNA-dependent RNA Polymerase 

Significance: RNA viruses represent some of the most significant pathogens known to mankind. The proposed research will contribute new knowledge about the function of a critical enzyme that is shared by all RNA viruses. This information is expected to foster the development of new antiviral drugs targeting that enzyme, thereby enhancing our ability to treat and prevent RNA viral diseases. 

PI: Sarah McDonald
CO-I: Leslie Laconte

Total Award: $386,400

Duration of Award: 5/2015 - 4/2017

Funding Agency: R21 Grant from NIAID/NIH

Title: Evaluation of RNActive®-based rotavirus vaccine in the gnotobiotic pig model of human rotavirus infection and diarrhea

Significance: Our overall goal is to develop next generation human rotavirus vaccines. The currently available human rotavirus vaccines are live oral vaccines and their efficacy and safety are affected by many factors. The objective of this project is to evaluate pre-clinically mRNA (RNActive®-based) rotavirus vaccines. We will determine the protective efficacy of the non-replicating parenteral rotavirus vaccine in the gnotobiotic pig model of human rotavirus infection and disease, and to characterize the mRNA vaccine-induced immune responses and identify the immune correlates of protective immunity. This is the first project in the “Joint development of vaccines against infectious diseases” program funded by CureVac GmbH and Bill & Melinda Gates Foundation.

PI: Lijuan Yuan

Total Award: $533,809

Duration of Award: 3/2015 - 8/2016

Funding Agency: CureVac GmbH, Tubingen, Germany

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: $308,000

Duration of Award: 1/2015 - 12/2018

Funding Agency: American Heart Association

Title: 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 of 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 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: $483,000

Duration of Award: 9/2013 - 8/2016

Funding Agency: NIH, NINDS

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: 7/2013 - 6/2017

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.

PI: X.J. Meng
CO-PI's: Yaowei Huang, Scott Kenney, Tanya LeRoith

Total Award: $1,585,850

Duration of Award: 7/2013 - 6/2017

Funding Agency: NIH, NIAID

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

Duration of Award: 1/2013 - 12/2017

Funding Agency: NIH, NIAID