Mississippi State University

NIH Research Projects · FY 2025 · 2021-08

7. Project Summary/Abstract Many of the organophosphate (OP) anticholinesterases, such as nerve agents, are highly toxic. Terrorist actions or accidents involving OPs could lead to mass casualties with potentially high levels of lethality. The current therapy consists of the muscarinic receptor antagonist atropine and an oxime reactivator of the inhibited acetylcholinesterase (2-PAM in the US). However, 2-PAM is not always effective at saving lives and cannot effectively penetrate the blood brain barrier, so 2-PAM can leave victims poorly protected. An improved oxime therapeutic is needed to counteract nerve agent lethality and assist with neuroprotection, so that both life and brain function may be preserved. Our laboratories have invented, patented and licensed a platform of substituted phenoxyalkyl pyridinium oximes that have shown better survival efficacy than 2-PAM and, unlike 2- PAM, attenuation of signs of seizure-like behavior and neuropathology in rats exposed to high levels of highly relevant nerve agent surrogates. Limited studies in male guinea pigs against sarin have also shown efficacy. With our current CounterACT Lead Identification U01 the efficacious compounds (the “actives”) have been down-selected to a lead and an alternate, with Oxime 20 being proposed as the Active Pharmaceutical Ingredient (API). The proposed project will build on the present survival efficacy, pharmacokinetic and API toxicity information in rats. Initially a superior vehicle for the API will be developed as a better solvent for the lipophilic API. A pharmacodynamic aim (Aim 1) will determine in rats (both sexes) whether a lower dosage of the API will be effective in promoting survival of lethal dosages of a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP; a G agent chemistry) and a VX surrogate (nitrophenyl ethyl methylphosphonate, NEMP; a V agent chemistry) alone or in combination with 2-PAM. A pharmacokinetic (PK) aim (Aim 2) will determine the PK of the API in the new vehicle, plasma protein binding and hepatic microsomal metabolism in rats of both sexes and will introduce studies of a larger non-rodent test species, the Gottingen minipig, both sexes. An oxime toxicity aim (Aim 3) will investigate dose responses of the API for gross pathological, histopathological, clinical chemistry and hematology adverse results in rats and minipigs of both sexes to identify a Maximum Tolerated Dosage and a No Observed Adverse Effect Level, as well as in vitro genotoxicity and drug-drug interactions for CYPs and transporters. A chemistry aim (Aim 4) will support the previous 3 aims by providing the synthesis of NIMP, NEMP and the API, produce a new vehicle with improved solvent properties, evaluate API stability, and provide initial plans for manufacturing and Chemical Manufacturing Controls. All studies will be non-GLP and will follow FDA guidance from pre-IND meetings. The overarching goal of this Lead Optimization project is to provide optimized pharmacological and toxicological information on our lead oxime in both sexes of two species that will prepare the API to move into advanced development toward FDA approval.

NIH Research Projects · FY 2025 · 2020-09

Currently licensed pneumococcal conjugate vaccines have been successful in preventing invasive disease; however, overall colonization rates have remained constant and serotype replacement by non-vaccine serotypes is now common. This suggests that most highly antigenic pneumococcal proteins may elicit strong, yet insufficiently protective immune responses against colonization. The long-term goal of this research is to identify novel vaccine candidates which can synergize with immunity induced by natural pneumococcal infections to provide universal serotype-independent protection against S. pneumoniae. The objective of this R15 renewal is to identify key pneumococcal surface protein (PSP) adhesins which are critical for colonization but fail to induce effective responses in the majority of the population, thereby contributing to stable colonization rates. The central hypothesis is that non-conventional PSP adhesins eliciting IgA response in human sera capable of inhibiting pneumococcal attachment, are ideal vaccine targets providing protective immunity against invasive pneumococcal infection. This hypothesis is based on strong preliminary evidence that demonstrates a low number of individuals develop antibodies that significantly inhibit pneumococcal attachment to respiratory epithelial cells while others do not. Identifying key colonization factors recognized by IgA responses in human sera capable of blocking adherence to host cells will help lead to new targets for serotype-independent protection against pneumococcal colonization. To accomplish this the following three specific aims will be pursued: 1) Identify PSPs eliciting IgA that inhibit pneumococcal adherence to host respiratory epithelial cells; 2) Determine the PSPs which play a critical role in pneumococcal adherence to host respiratory epithelial cells and their mechanism of attachment; 3) Determine protective effect of PSPs vaccine targets in a mouse model of pneumococcal infection. This approach is innovative because it will identify previously unknown non-traditional PSP adhesins critical for colonization, the prerequisite step to invasive disease, while also identifying their cognate receptors on host cells, thereby clarifying the mechanisms of attachment. This work is significant because it will provide new vaccine candidates to limit the large population of humans colonized with pneumococcus, thus overcoming the shortcomings of current vaccines. The streamlined workflow for developing a novel vaccine, which incorporates basic and advanced techniques in microbiology, molecular biology, biochemistry, immunology, and reverse vaccinology, will engage undergraduate and graduate students from across Mississippi in the advancement of biomedical research. This effort fulfills the goals of the AREA grant program and contributes to the mission of the NIH by applying scientific knowledge to enhance human health.

NIH Research Projects · FY 2024 · 2020-09

Abstract In response to the FDA’s Laboratory Flexible Funding Model program announcement, the Mississippi State Chemical Laboratory (MSCL) has submitted a robust proposal titled “Enhancement of Mississippi’s Capabilities in Integrated Food Safety Partnerships.” This plan encompasses six projects:  Discipline B: Chemistry, Analytical Track 1. Food Defense (Years 1-5)  Discipline B: Chemistry, Analytical Track 2. Human Food Product Testing (Years 1-5)  Discipline B: Chemistry, Analytical Track 3. Animal Food Product Testing (Years 1-5)  Discipline D: Special Projects 1. Sample Collection (Years 1-5)  Discipline D: Special Projects 2. NFSDX and ORAPP Integration (Year 1 only)  Discipline D: Special Projects 3. Method Development/Validation (Year 2 only) Overall Objective: Strengthen Mississippi’s Integrated Food Safety System. A truly integrated food safety system depends on a mutual reliance between state and federal regulatory agencies. In order for this reliance and integration to prevent and effectively respond to foodborne or food contaminant incidents, there needs to be certifications and universal standards, food safety program collaboration and communication, and competent staff and continuous improvement training. This funding opportunity and the MSCL’s proposal encompasses these criteria. With this funding, the MSCL will be able to expand the surveillance of food products, begin surveillance testing of animal feed products for chemical and toxin contaminants, and expand the MSCL’s scope of accreditation.

NIH Research Projects · FY 2025 · 2017-08

Project Summary The Mississippi Veterinary Research and Diagnostic Laboratory (MVRDL) is a full service, AAVLD accredited, all species, central reference laboratory. Our work force includes 10 faculty members (pathologists, poultry veterinarians, microbiologists, virologists, and molecular biologists) and approximately 28 staff positions. The Microbiology section personnel consists of a section supervisor (DVM, MS and PhD in Veterinary Sciences) with more than 30 years of clinical and research microbiology experience, a laboratory coordinator with 25 years of microbiology experience and two medical technologists with over 10 years of clinical laboratory experience each. The section analyzes samples from approximately 3000 accessions per year from which over 9000 procedures (aerobic cultures, anaerobic cultures, antimicrobial susceptibility tests) are completed. The Molecular Diagnostics section personnel consists of a section supervisor (MS and PhD in Animal Nutrition and Veterinary Medical Science) with more than 7 years of clinical and research molecular diagnostic experience, two laboratory technologists with more than 15 years of molecular diagnostic experience, and one laboratory technologist with 1year of molecular diagnostic experience. The section analyzes over 2500 accessions per year from which over 6000 procedures (PCR and gene sequencing) are completed. Through our participation in this collaborative agreement, we agree to participate in the three key project areas: (1) Participation in FDA/Vet-LIRN sample analysis (2) Providing analytical data for potential regulatory use (3) Participation in small-scale method development, method validation and matrix extension work as determined by the VPO. The MVRDL participates as a source lab for the Vet-LIRN antimicrobial resistance and whole genome sequencing projects. MVRDL has the capacity and is willing to offer its’ services to increase the capacity of the VPO in handling increased sample workflow during emergencies. MVRDL is committed to performing these services in an efficient, accurate and timely fashion and to reporting the results to the required agency.

NIH Research Projects · FY 2025 · 2000-09

Mississippi State University College of Veterinary Medicine (MSU-CVM) and Tuskegee University College of Veterinary Medicine (TUCVM) have developed a partnership during the previous funding period of this T35 program that has been effective and which both institutions wish to continue. This will be the twentieth year of T35 funding for MSU-CVM and the fifth year for TUCVM, which had not previously had T35 funding. Our long-term goal in this T35 is to contribute to the national capacity of veterinarians in biomedical research by engaging and educating veterinary students in short-term research training early in their curriculum. In the previous funding period, we utilized the joint collaboration to train 46 and 11 veterinary students at MSU-CVM and TUCVM, respectively. The immediate goal of this application is to involve veterinary students in short-term research training opportunities supported by the Ruth L. Kirschstein NRSA Short-Term Institutional Research Training Grants (T35) program. Again MSU-CVM and TUCVM propose to administer a Summer Research Experience (SRE) Program to recruit and train veterinary students in biomedical research. Our program will provide summer research experiences for 12 veterinary students each year that have completed their freshman, sophomore, or junior year in an AVMA-accredited veterinary curriculum with 9 training positions at MSU-CVM and 3 training positions at TUCVM. The proposed training will consist of a continuous 12-week block of time in summer. The program will have three major components: 1) research conducted under the mentorship of an active faculty researcher, 2) educational activities in research, career development, and leadership, and 3) training and experience in preparation of scientific presentations. MSU-CVM and TUCVM will take several steps to ensure the program is jointly operated: both colleges will participate in selecting trainees, educational activities will be jointly administered, and trainees will be assigned to MSU-CVM or TUCVM based on individual research interests. We have operated successfully in this manner in the previous funding period and propose to continue this collaboration in the next funding period, which this has been facilitated by outstanding institutional support from both MSU-CVM and TUCVM. Our colleges have unique research programs to give trainees experience in toxicology, epidemiology, translational research, genomics/functional genomics, computational biology, infectious disease, oncology, and food safety.