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Notable Grants

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Despite technological advancements, the 5-year survival rate for advanced HNSCC has remained stagnant for the past three decades. The FDA has approved immune checkpoint inhibitors (ICIs), including pembrolizumab and nivolumab, for the treatment of recurrent and metastatic HNSCC. While immunotherapy can induce durable remissions, only 15–20% of patients respond to treatment. There is growing interest in combining ICIs with chemotherapy or radiotherapy to enhance therapeutic efficacy. However, this approach has faced significant setbacks in recent clinical trials. Emerging studies suggest that the lack of activated dendritic cells (DCs) in tumors is a major reason for immunotherapy failure. Therefore, developing therapeutic strategies that not only eliminate cancer cells but also release stimulatory factors to promote intratumoral DC maturation and migration holds great promise for enhancing tumor sensitivity to immunotherapy. Our goal is to develop a novel adjuvant nanotechnology based on 7-dehydrocholesterol (7DHC)- encapsulated synthetic low-density lipoproteins (7DHC-LDLs) to boost anti-tumor immunity when used in combination with ICIs. 7DHC, a cholesterol analog, exhibits the highest rate of free radical chain propagation among known lipid molecules. Our preliminary data demonstrate that 7DHC-LDLs, like natural LDLs, accumulate in tumors by binding to the LDL receptor, which is upregulated in HNSCC. In the presence of reactive oxygen species (ROS), 7DHC triggers and amplifies lipid peroxidation in cell membranes, leading to ferroptotic cell death. In addition, our data suggest that cancer cells killed by 7DHC release danger-associated molecular patterns (DAMPs) and pro-inflammatory cytokines, which activate DCs and enhance tumor-reactive T cell priming, even in immunologically “cold” tumors. In this project, we will evaluate the pharmacokinetics and biodistribution of 7DHC-LDLs in orthotopic HNSCC models. We will test whether the innate adjuvant effects of 7DHC-LDLs can be leveraged to enhance the efficacy of anti-PD-L1 checkpoint blockade. Finally, we will perform a comprehensive analysis of the tumor microenvironment to elucidate the impact of this combination therapy.

Funder: NIH

Amount: $3,072,426

PI: Jin Xie, Franklin College of Arts and Sciences, Department of Chemistry

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Notable Grants

Drugs that increase O-GlcNAc have been developed and proceeded into clinical trials. Notably, O-GlcNAc is found on neurodegeneration associated proteins, like tau and α-Syn, and has been shown to inhibit their amyloid aggregation and associated pathology in vitro and in mouse models. However, little is known concerning any differences in O-GlcNAc levels in PD versus healthy brain tissues or whether O-GlcNAc modified α-Syn is excluded from corresponding insoluble inclusions. This project will directly fill in this missing knowledge at the level of the proteome, α-Syn modification levels, and the individual sites of O-GlcNAc on α-Syn. If we find that O-GlcNAc levels on disease relevant proteins are altered and/or that O-GlcNAc is only associated with soluble α-Syn, this information will provide strong supporting evidence to enable data-driven targeting of OGA as a potential therapeutic strategy.

Funder: Michael J. Fox Foundation 

Amount: $638,256 

PI: Robert Wells, Franklin College of Arts and Sciences, Department of Biochemistry and Molecular Biology 

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Notable Grants

There is an urgent agricultural need for novel approaches to combat the billions of dollars lost annually to the devastating root-knot nematode, an obligate sedentary endoparasite and

global threat to food and fiber crop production. The focus of this project is to resolve the mystery of the root-knot nematode feeding tube, a unique nematode-produced structure that forms within the cytoplasm of plant root cells selectively transformed into giant-cells by the nematode to serve as a nutrient sink leading to successful parasitism. Feeding tubes produced by all species of root-knot nematodes are essential for efficient withdrawal of nutrients from the cytoplasm by the sedentary adult females which require intensive nourishment for several weeks during the production of hundreds of eggs. While the feeding tube has been described at the ultrastructural level, its composition and mechanism of assembly remain an enigma. A combination of immunohistochemistry, structural biology, and protein interaction studies coupled with host-delivered RNA interference is proposed to identify the nematode proteins involved in feeding tube formation and translate this knowledge to develop novel root-knot nematode resistance in crop plants. The composition of feeding tubes and the underlying mechanism of their assembly is currently unknown and presents a truly transformative opportunity for a deeper understanding of root-knot nematode parasitism. The underlying hypothesis is that once adult root-knot nematode females have established giant-cells they secrete one or more proteins through their stylet into these cells that self-assemble into a feeding tube essential for efficient nutrient uptake. A molecular and biochemical understanding of the mechanism of feeding tube formation will enable the development of innovative, broad-spectrum strategies for combating this destructive agricultural pathogen. This project will provide new insights into the molecular basis of feeding tube formation by root-knot nematodes, which in turn will provide critical insight into how these nematodes successfully parasitize a wide range of plant hosts to aid in the design of novel and broad resistance in crop plants. PI Mitchum will partner with the State Botanical Garden of Georgia for field trip adventures and summer camp activities to improve STEM education through hands-on activities that will bring awareness to the hidden enemies lurking below ground that impact our food supply.

Funder: USDA NIFA 

Amount: $800,000 

PI: Melissa Mitchum, College of Agricultural and Environmental Sciences 

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Notable Grants

The purpose of this cooperative agreement is to evaluate the antiviral therapeutic potential of tannins against highly pathogenic avian influenza (HPAI) as natural anti-viral supplements and immunomodulators in poultry. Tannins, plant-derived polyphenolic compounds and their metabolites, have highly effective antiviral effects against broad spectrums of pathogenic viruses including influenza virus H3N2, H5N3, herpes simplex virus-1, Newcastle disease virus and adenovirus1-5. Thus, the proposed studies will develop effective therapeutic strategies with natural antiviral bioactive compounds to prevent poultry from HPAI infection and strengthen poultry immune system, maintaining sustainable poultry production and U.S. food security. Activities include 1) Evaluating antiviral effects of tannins against HPAI in vitro to elucidate the anti-HPAI mechanisms (mode of action) of tannins; 2) Evaluating effects of tannins on immune modulation in chicken macrophage cells and/or chicken mesenchymal stem cells under HPAI infection conditions; 3) Optimizing tannin inclusion level for the efficient growth and immunoprotecting potential in laying hens and turkeys; 4) Evaluating anti-HPAI effects of tannins in HPAI virus challenge studies with laying hens and turkeys (BSL3). Deliverables are obtaining data on anti-HPAI effects of tannins, their antiviral mechanisms, immunoprotected effects of tannins, optimization of tannin inclusion, HPAI challenge data, performance, mortality, and publications.

Funder: USDA PHIS 

Amount: $1,716,819 

PI: Woo Kyun Kim, College of Agricultural and Environmental Sciences 

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Notable Grants

By integrating innovative biotechnology and a comprehensive understanding of viral-host interactions, this approach aims to significantly mitigate the threat of highly pathogenic avian influenza (HPAI) in poultry through oral prophylaxis. This agreement evaluates the potential of natural compounds, alone and in combination, as immunomodulators and antivirals against HPAI. We will test each compound and compound combination for their safety and mechanisms of action in vitro using different tissue culture systems. Follow up studies will optimize dosage and delivery routes (via feed or water) and assess their efficacy against HPAIV infection in laying hens. In addition, we will investigate the immune response stimulated by compounds, monitor viral evolution, and study the impact of interventions on the microbiome. Finally, compound combinations will be assessed in chickens for their synergistic effect and to establish improved regimens to promote animal health. Deliverables include compounds with proven effect in increased resistance to HPAIV, administration regimens for compound combinations, clinical, immunological, and histopathological data, viral evolution and microbiome analysis, scientific publications and other reports that will help advance licensing of the compounds for agricultural use. The project will validate interventions to increase resistance to HPAIV infection, mortality, and transmission in poultry, paving the way for targeted therapies that promote a healthy balance and resilience against infections. Hence, the project will benefit the US egg and poultry industries, representing a substantial investment in the future of both animal and human health, with the potential to yield transformative results that extend far beyond avian influenza.

Funder: USDA APHIS 

Amount: $1,789,340 

PI: Daniela de Souza Rajao, College of Veterinary Medicine 

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Notable Grants

Driven by the urgent need to safeguard the US poultry industry from the devastating impact of Highly Pathogenic Avian Influenza (HPAI), this project leverages a powerful synergy between the University of Georgia’s cutting-edge research capabilities and the established industrial expertise of CEVA Animal Health and BioStone Animal Health to deliver a transformative solution: the first US-approved, mass-vaccination-ready modified live virus (MLV) vaccine against HPAI, accompanied by a comprehensive suite of companion DIVA diagnostics. This involves generating an H5N2 MLV candidate that is stable, grows to high titers (≥10^6 TCID50/mL), and elicits protective immune responses against aggressive H5N1 HPAI challenge after a single dose. The H5N2 MLV will be designed with a chimeric segment and incorporate specific molecular markers with unique sequences. Molecular diagnostic tools, including real-time RT-qPCR and NA-based serological assays, will also be developed to differentiate infected from vaccinated animals (DIVA). Key deliverables include a US-approved, mass-vaccination-ready influenza MLV against HPAI, along with reports, peer-reviewed publications, and other documentation necessary for vaccine and diagnostic tool approvals. The expected outcome is a reduction in the impact of HPAI virus pathogenesis and transmission in commercial poultry premises, specifically layer and turkey operations. The successful vaccine will stimulate humoral, mucosal, and cellular immunity, offering more effective protection against diverse HPAI strains. This project will positively impact the broader US poultry industry by providing a valuable tool for controlling and preventing HPAI outbreaks. Sub-awardees, including CEVA Animal Health and BioStone Animal Health, play crucial roles. CEVA will contribute their expertise in generating the first licensed MLV against avian influenza for poultry use in the US. CEVA and BioStone will also develop nucleic acid-based and ELISA-based diagnostic assays, respectively, providing an all-in-one vaccine and differential diagnostics platform.

Funder: USDA APHIS 

Amount: $1,999,873 

PI: Daniel Perez, College of Veterinary Medicine 

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Notable Grants

American alligators (Alligator mississippiensis) are managed quite differently than most other fish and wildlife species in the United States. As reptiles, they do not fall within the ‘fur and feathers’ category traditional to state wildlife management, which typically receives the bulk of attention, management, and funding. Despite harvest in aquatic habitats, they are also not considered a fishery and are not managed as such. The unique nature of their status has resulted in comparatively less research and management, contributing to significant uncertainties which can hamper decision making. Such challenges are only exacerbated by paradoxical social views of alligators. They are simultaneously considered a nuisance animal with the capacity to threaten human safety, a species of conservation focus due to previous listing under the Endangered Species Act, and a desired hunted species. In some locations, alligators are a flagship species, integral to the identity and tourism of places like Everglades National Park. Such tradeoffs understandably make decision making difficult, which is only compounded by the lack of information and resources dedicated to alligator management and study. Further research into the status and uncertainties of alligator populations falls squarely within the goal of the State and Tribal Wildlife Grants (SWG) Program—to ensure common species remain common and to prevent species from falling through the cracks. Monitoring and understanding alligator populations is crucial to maintain healthy populations, but also because of their status as an indicator of ecosystem health. Living in a variety of wetland habitats, alligators are both apex predators and ecosystem engineers. Alligator populations are particularly sensitive to environmental changes and overharvesting, making them valuable indicators of ecosystem conditions and the effectiveness of management interventions. Studying these populations, however, presents several challenges. Alligators’ long life spans, which can exceed 60 years in the wild, mean that many individuals will outlive a typical research program, thus limiting our understanding of population dynamics over their lifetimes. Given the benefits of alligators to the ecosystem, hunters’ desire for alligator harvest in Georgia, and the SWG goal to prevent species from becoming endangered, research to gain a better understanding of alligator population size and dynamics is needed to enable Georgia DNR to make harvest management decisions that balance hunter satisfaction and population sustainability. The complex social views and unclear management status of alligators, combined with a long-life history and challenges of field studies, has led to significant uncertainties regarding alligator populations in the Southeast. Improved understanding of alligator populations will support better decision-making on harvest management to prevent overexploitation, while also considering the public desire for tags. The objective of this work is to estimate alligator population size and structure with simulations of various harvest quotas in the state of Georgia. Multiple types of data, collected by Georgia Department of Natural Resources (DNR) over decades, will be synthesized into an integrated population model. The model will be customizable to the type and amount of uncertainty based on available data and information from species experts. Additionally, we will simulate the population under varying harvest levels to test the sensitivity of population to harvest to inform Georgia DNR’s alligator tag allocations. Building on the population model, the second objective is to identify key areas of uncertainty in our knowledge of Georgia alligator populations (e.g., age, location, movement) through value of information analysis (VoI). Such identification will help inform the allocation of research efforts to reduce uncertainty and inform optimal decisions for harvest management. The third objective is to develop an optimal monitoring plan for alligator populations considering limited agency resources. This objective will focus on creating an achievable monitoring plan to inform management decisions for alligators in Georgia under the constraints of limited agency funding and personnel. The plan will integrate the results of the first two objectives to guide monitoring recommendations, while also capturing the limitations associated with on the ground monitoring activities. This research is expected to significantly improve the understanding of alligator populations in Georgia, providing valuable insights for effective harvest management and informed decision-making. By integrating decades of data into an integrated population model (IPM), we will estimate population size and structure and quantify the uncertainty surrounding these estimates. Simulations of varying harvest levels will help inform more accurate harvest quotas, while a value of information (VoI) analysis will guide DNR in prioritizing research efforts to reduce the most critical uncertainties. This work will enhance the ability to balance the need for sustainable harvest management with public demand for alligator tags, ultimately contributing to more informed, evidence-based conservation strategies. Furthermore, the findings will be directly applicable to DNR’s ongoing research program, with recommendations tailored to optimize resource allocation and improve future population monitoring efforts. Broadly, this work will serve as an example of effective estimation for data deficient species and science-driven research guidance.

Funder: Georgia Department of Natural Resources

Amount: $247,824

PI: Kelly Robinson, Warnell School of Forestry and Natural Resources

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Fruit ripening is a highly regulated developmental process. From a human diet perspective, fruit are a reservoir of antioxidants and vitamins. Until recently, a few fruits have served as model systems to investigate mechanisms associated with fruit ripening. However, aspects of ripening physiology and their regulation by transcription factors and hormones are fruit-specific, and show substantial variability across fruits. Blueberry production has increased worldwide due to its popularity as a fruit rich in antioxidants. However, ripening physiology is poorly understood in blueberry. Hence, advances in breeding fruit with high quality and development of tools to manipulate ripening and fruit quality have been limited. In this proposal three aims are presented to advance our understanding of blueberry ripening physiology. In Aim 1, we propose to investigate the spatiotemporal dynamics of ripening using analyses of expression of ripening-related genes, metabolite compositions, and hormone concentrations. In Aim 2, we propose to investigate the role of candidate blueberry ripening-related transcription factors. We will functionally validate their roles by overexpression in tomato and blueberry and identify their targets using ChIP-Sequencing in blueberry. In Aim 3, we propose to fill gaps in our understanding of hormonal regulation of blueberry fruit ripening, primarily that of abscisic acid and auxin, and their interactions with ethylene. Collectively, the proposed work will enhance our understanding of blueberry ripening physiology. This knowledge will help improve blueberry productivity and sustainability, and result in an increase in yield and fruit quality.

Funder: USDA NIFA

Amount: $649,992

PI: Savithri Nambeesan, College of Agricultural and Environmental Sciences

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Notable Grants

The objectives of this project are to:

1. Investigate the mechanisms of pathogenicity of Eimeria field isolates that cause poultry coccidiosis and assess the bird responses to infections. The team will (1) propagate and harvest pure cultures of Eimeria isolates to obtain high quality DNA for generating full genome sequences of Eimeria parasites; (2) test the ability of divergent isolates to induce coccidiosis in commercial birds and measure the differential responses to individual and mixed infections; and (3) study the influence of host genetics on resistance, susceptibility, and tolerance to field Eimeria isolates, in combination with defined environmental conditions that influence the birds’ microbiome and intestinal integrity leading to pathological status and pre-disposition to secondary infections.

2. Identify and characterize the molecular mechanisms of Clostridium perfringens infections resulting in necrotic enteritis and develop effective vaccines. The team will (1) employ next-generation sequencing to fully characterize the genomes of C. perfringens isolates (collected from field cases in the Southeast and mid-Atlantic regions) causing necrotic enteritis and comparatively analyze those sequences to identify virulence factors that contribute to the development of clinical and subclinical enteritis; this will allow a better understanding of the incidence of necrotic enteritis in the context of coccidiosis in commercial poultry; (2) test the effects of those isolates on the pathological and immunological responses of chickens with divergent genetic backgrounds, which could further delineate the differential responses in commercial chicken breeds to aid in identifying and using species genetics in commercial operations; (3) use the identified virulence factors as targets for designing and developing vaccines (based on already established nanoparticle platforms) as alternative measures to antibiotics for controlling enteritis.

3. Test and determine effective non-drug alternatives to antibiotics for the prevention and treatment of coccidiosis and necrotic enteritis. For Objective 3, there is an impetus to find effective non-drug alternatives, and the team will employ an integrated approach involving applied studies to better understand the mechanistic actions of several alternative candidates on performance, physiological, microbial, immunological, and metabolic responses of the host. In vivo (birds) and in ovo (late-stage embryos) trials will investigate the applications of well-defined probiotics, prebiotics, postbiotics, and phytogenics during coccidiosis and necrotic enteritis to characterize these critical physiological changes that directly impact bird health and performance. Specific measurable variables at the enteric and systemic levels will collectively provide strong host response correlates that can be utilized in translational studies to refine the applications of such effective alternatives in commercial settings.

Funder: USDA ARS

Amount: $728,944

PI: Todd Applegate, College of Agricultural and Environmental Sciences

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Notable Grants

Global forests are increasingly at risk from multiple, synergistic stressors, threatening both timber production and ecosystem services. While trade-offs between productivity and resilience are well-documented, studies investigating belowground stress response mechanisms are limited, particularly for long-lived tree species. Furthermore, the genetic basis of these traits and the degree to which genetic co-associations may constrain adaptation and limit genomic selection in tree breeding programs is unknown. The goal of this project is to assess productivity-resilience tradeoffs under the combined effects of drought, fire, and pathogen stress across southern yellow pine species. We address these knowledge gaps with the following objectives. (1) Assess coordinated, whole tree productivity and functional trait responses to multiple stressors (drought, brown spot needle blight, and fire). (2) Identify genetic associations with stress response mechanisms, and test for evolutionary constraints between productivity and resilience traits using genetic co-association networks. (3) Develop multi-trait genomic prediction models to identify optimal targets for genomic selection and tree breeding programs. (4) Work with pine breeding cooperative partners to develop performance rating sheets to assist landowners, forestry and restoration practitioners in selecting seed stock that meets their goals along the productivity-resilience spectrum. This project is directly aligned with the program priorities of improving the sustainable management of forests under the threats of climate change, pathogens, and increased environmental pressures. Findings will provide critical information to optimize seed selection, enhance the success of forest restoration, and support tree breeding programs in improving forest sustainability in a rapidly changing world.

Funder: USDA NIFA

Amount: $749,038

PI: Helen Bothwell, Warnell School of Forestry and Natural Resources