Author: orandall

Degenerative photoreceptor (PR) cells contribute to vision loss in AMD patients. The lack of effective models to study PR repair and maintenance is a critical gap in our knowledge, limiting current therapeutic strategies to prevent retinal damage and reinstate vision in AMD. Previous data revealed an ATF6-dependent loss of cone PR outer segments (OS), correlated to dysfunctional mitochondria and loss of critical ciliogenesis genes. While ATF6’s role in mitochondrial health and OS formation is not characterized, its pharmacological modulation shows promise in repairing cone PR function in AMD. We hypothesize that that ATF6’s transcriptional network directly regulates cone PR OS formation by improving mitochondrial health and upregulating essential ciliogenesis genes. We aim to define ATF6-dependent mitochondrial defects in AMD relevant retinal cell types (RPE, PR, RGC, Müller glia) and investigate changes in mitochondria morphologies and function (Aim 1.1). ATF6-dependent targets, such as RAB23, MARS2, OPA2, which have a critical role in mitochondrial stability, will be confirmed through biochemical and molecular analysis. Using ATF6 control and mutant retinal organoids, we will evaluate ciliogenesis components and perform rescue experiments using ATF6 activators to elucidate their therapeutic potential (Aim 1.2). Electron and confocal microscopy, along with patch clamp recordings, will assess functionality in newly generated cone PR cells. Aim 2; using the bi-foveated, cone-rich brown anole lizard, we created atf6 Mutant lizards, confirming the absence of cone PR OS. Advanced imaging will examine cone PR OS and foveal morphology. Retinal analysis includes a characterization of all AMD-affected cell types through biochemical and molecular data collection, with bulk RNAseq analysis in progress (NovoGen). The atf6-dependent rescue of lizard cone PR OS’s in Mut animals will be assessed through micro-injection of AV[atf6(N)] into the intravitreal space. Strong collaborations assist with OCT, AOSLO images, and ERG readings. Our research combines stem cell technologies and the lizard model to explore an alternative regulatory mechanism for cone OS development and regeneration using the ATF6 transcriptome. Alongside current AMD therapies like RPE cell replacement, our project offers a potentially synergistic approach to treat AMD pathologies.

Funder: Brightfocus Foundation

Amount: $449,986

PI: Heike Kroeger, Franklin College of Arts and Sciences, Department of Cellular Biology

The health impact of food processing is a relevant and timely topic in human nutrition as processed food constitutes a large part of the world’s food consumption. Approximately 60% of food in the US and UK is ultra-processed. The term ultra-processed food indicates formulations generally including five or more ingredients, mostly of cheap industrial sources of dietary energy, nutrients, and additives, using a series of processes to manufacture, and containing minimal whole foods. In humans, a direct association has been found between consumption of ultra-processed foods and specific diseases such as cardiovascular disease, obesity, neurodegenerative disorders, etc. and with all-cause mortality. Advanced glycation endproducts (AGEs) and advanced lipoxidation endproducts (ALEs) represent classes of pro-oxidants in foods, the presence of which is promoted by food processing at high temperatures. A large body of evidence supports that AGEs are involved in the pathogenesis of diseases and their complications. Dietary AGEs are linked to excess radical oxygen species, high oxidative stress, cytokine synthesis, and inflammation which can cause obesity, cancer, neurodegenerative disorders, osteoarthritis, chronic kidney disease, and other diseases. Many commercial dog foods by definition are ultra-processed in that they include more than five ingredients, are manufactured using a series of processes, and containing minimal whole ingredients. In one study evaluating dog and cat foods, it was estimated that on a metabolic body weight basis compared to humans consuming a high ultra-processed Western diet, dogs consume approximately 120 times and cats approximately 40 times the amount of AGEs on average daily.

The objectives of this study are to evaluate the influence of food processing using three diets that are identical in composition but processed in three different ways. We hypothesize that dogs that consume a minimally processed diet when compared with highly processed diets will show lower dietary AGEs, plasma AGEs, urinary AGEs, urine protein-to-urine creatinine ratios, blood glucose, serum insulin, serum fructosamine, receptors for AGEs, and plasma inflammatory biomarkers. Thirty clinically healthy dogs that are relatively age-matched will be fed a standard dry (kibble) diet for 4 weeks. They will then be randomized into one of three diet groups for 8 weeks, and samples will be collected at the end of this period. Comparisons will be made between diet groups and between the start and end of the treatment period.

Funder: The Farmer’s Dog

Amount: $521,419

PI: Joseph Bartges, College of Veterinary Medicine

Beginning in 2020, the Georgia Department of Community Supervision (DCS) has implemented a person-centered supervision (PCS) model for officers. This model seeks to meet the dual roles of DCS for accountability and rehabilitation by enhancing the voices of persons on probation and parole while under supervision through relying on elements of procedural justice, technology, and evidence-based research in communities across Georgia. Given the scale of the PCS model, there is a need to develop an instrument to consistently assess the quality and outcomes associated with PCS throughout the state, to ensure the model is effective and delivered in an appropriate manner. The first goal of this proposed evaluation will be to establish an internal instrument to assess PCS program quality across all 51 judicial districts in the state of Georgia. Instrument development will be conducted in four stages (1) collaborative, systematic examination of existing assessment instruments and related documents that may capture PCS practices relevant to the state of Georgia, (2) Pilot testing and refinement, (3) Instrument demonstration and (4) Instrument validation. Additionally, to our knowledge, no systematic exploration of how the PCS model relates to criminal justice and public safety outcomes currently exists. Thus, the second goal of this evaluation proposal is to examine outcomes of the PCS model in the State of Georgia using existing data provided by the Georgia Department of Supervision and other publicly available data. The results from the proposed evaluation will assist DCS in establishing an evidence-base for the PCS model as well as provide a solid foundation for future internal assessment throughout the state.

Funder: Georgia Department of Community Supervision

Amount: $661,139

PI: Orion Mowbray, School of Social Work

Livestock integration can restore synergies between animal and plant agriculture, long the cornerstones of sustainable farming. For example, pastured chickens (Gallus domesticus) might feed heavily on pests and weeds while generating nutrient-rich manure, benefiting crops. But chickens also might eat beneficial predatory, detritus-feeding or pollinating arthropods, or spread harmful bacteria (e.g., Campylobacter, Salmonella) that endanger food safety. Unfortunately, there have been surprisingly few holistic studies of pastured chickens’ ecological roles, both good and bad, on highly diversified mixed-vegetable farms. This leaves growers unable to predictably weigh the benefits and risks of crop-chicken integration. Working in cooperation with our grower collaborators, we propose to: (1) Detail chickens’ feeding on pest and beneficial insects, and weeds, through molecular analysis of dietary-DNA remains in chicken feces, (2) Track likely sources of chicken exposure to Salmonella and Campylobacter bacteria using whole-genome pathogen sequencing, and (3) Quantify the birds’ net impacts on arthropods, weeds, and soil microbes, through on-farm chicken exclusion experiments. Our “Chicken Dinner” outreach effort will recruit grower citizen-scientists from across the southeastern U.S. to submit samples from their own pastured flocks for diet and pathogen analysis, so they can assess the ecosystem services (and disservices) their birds are providing. Our ultimate goal is to provide growers with practical tools to maximize the benefits of pastured chickens, while minimizing any dangers, as part of whole-farm planning. We address both Sustainable Agroecosystem priorities by developing new approaches to significantly increase several ecosystem services, while improving managed system biodiversity and sustainability.

Funder: USDA NIFA

Amount: $749,434

PI: William Snyder, College of Agricultural and Environmental Sciences, Department of Entomology

Impulsivity refers to the propensity toward rapid action without forethought of the consequences and devaluing rewards that are delayed in time in favor of immediate gratification. Food impulsivity is associated with obesity and binge-eating disorder and can counter efforts to make healthy food choices. Regions of the brain that regulate food impulsive behaviors, such as the hippocampus and medial prefrontal cortex (mPFC), undergo neuroplasticity during adolescence and emerging evidence indicates that hippocampal-dependent memory is vulnerable to the deleterious impact adolescent consumption of “Western diets” (WD) high in saturated fat and added sugars. Furthermore, hippocampal dysfunction associated with adolescent WD consumption is not easily reversible by switching to a healthy diet during adulthood. We propose that adolescent consumption of a WD impairs hippocampal development leading to increased impulsive eating behavior during adulthood. Our unpublished preliminary data are consistent with this hypothesis and show that female rodents fed a WD during adolescence have increased impulsive actions when responding for a palatable food reinforcer during adulthood. Proposed work will extend this model to males and will also determine whether females and males on a WD during adolescence show a propensity to select smaller and more immediate food rewards over waiting for a larger payoff (delay discounting test of impulsive choice). Our additional preliminary in vivo calcium imaging data reveal differential calcium dynamics in the ventral CA1 hippocampus (vCA1) prior to impulsive vs. non-impulsive food-directed action, with analogous effects observed in the nucleus accumbens shell (ACBsh). Building off these

findings, we propose to determine how specific hippocampal circuits (vCA1->mPFC and vCA1->ACBsh) known for their role in modulating reward behaviors, inhibitory control, and impulsivity, are impacted by an adolescent WD consumption in rats. To determine whether behavioral intervention can reverse the long-lasting increased food impulsivity associated with adolescent WD, we will also investigate whether aerobic exercise, which is known to attenuate WD-induced hippocampal-dependent memory impairments, can attenuate adolescent WD-induced food impulsive actions and choices. Further, we have previously shown that the incretin hormone glucagon-like peptide-1 (GLP-1) acts on a vCA1->mPFC pathway to reduce food impulsive behavior. Thus, here we propose to determine whether clinically relevant FDA-approved GLP-1 analogue treatment reverses or attenuates adolescent WD-induced food impulsive behaviors. This proposal is sufficiently powered to determine sex differences for all experiments, and results from these studies will provide a critical contribution to obesity developmental neuroscience research and advance our understanding of how diet impacts eating behaviors.

Funder: National Institutes of Health

Amount: $3,583,438

PI: Emily Noble, College of Family and Consumer Sciences

Initial findings on genomic selection indicated substantial improvement in major traits, such as performance. Under genomic selection, the selection accuracy increases, and the generation interval decreases, accelerating the selection response. However, recent unofficial reports indicate an increased frequency of deterioration of unselected or negatively correlated traits. This phenomenon may arise due to the mismatch between the accelerated gains and the overlooked changes in correlated traits. Because of the rapid turnover of genomic selection, heritabilities for production traits decline faster, and the genetic antagonism between production and fitness traits intensifies. Therefore, it is crucial to look for unexpected changes in economically important traits and take rapid steps to prevent further declines, especially in secondary traits. However, estimating variance components and genetic parameters over time to investigate such changes with many genotyped animals is prohibitive. Without that, assessing and preventing the negative impact of genomic selection becomes challenging. Therefore, we propose to:

1) Extend the limits of current methods to estimate variance components with large genomic datasets;

2) Develop new methods to estimate genetic correlations and heritabilities based on crossvalidation equations that use predictive ability or linear regression methods, which will work with millions of genotyped animals;

3) Test the extended/new methods on various datasets to identify the combination of traits with anticipated negative effects of genomic selection.

This project will provide tools for the US industry to identify and avoid unexpected changes due to genomic selection, which aligns well with the priorities of Program A1201 – “Animal Breeding, Genetics, and Genomics.”

Funder: USDA NIFA

Amount: $650,000

PI: Daniela Lino Lourenco, College of Agricultural and Environmental Sciences, Department of Animal and Dairy Sciences

Child abuse and neglect (CAN) is a pressing and preventable public health issue with negative lifelong consequences, including early deaths. Children living in economically disadvantaged families and communities are at high risk for CAN. Economic support policies may be effective strategies towards reducing CAN through strengthening families’ financial well-being and reducing related stress. Because states vary in policy selection and implementation (e.g., eligibility and spending), understanding the effects of varying state-level economic support policies can inform the larger-scale implementation of economic policies to prevent CAN. Yet, there is a lack of research examining the causal effects of state economic support policies on CAN prevention. Also, little effort has been made to bridge macro-level policy evaluation with community-based CAN prevention strategies. Since the Covid-19 pandemic, many states have adjusted pre-existing programs and enacted Covid-related support policies (e.g., eviction moratoria and extended unemployment benefits). Evaluating the impact of changing policies on

CAN during pre- Covid, Covid, and Covid-recovery eras can help determine how to direct economic support resources to families at risk of CAN during recovery and plan for future disasters. Leveraging a natural experimental design with nationwide data, along with a community-based participatory design, this study will 1) identify and synthesize state-level economic support policies during pre-Covid, Covid, and Covid-recovery eras, to examine how these policies, individually and in synergy with each other, impact county-level CAN report rates; 2) investigate how states’ policy effects on CAN are mediated by county-level poverty and unemployment rates, and whether the effects vary by age, gender, race/ethnicity, rural/urban status, and CAN subtype; 3) develop and implement advocacy strategies with local communities to increase access to empirically informed economic support services that prevent CAN. To accomplish the proposed project goals, the PI will receive mentorship from a group of interdisciplinary experts, including Drs. Melissa Jonson-Reid, Derek Brown, and Patricia Kohl, take full advantage of the extensive resources at the NIH-funded Center for Innovation in Child Maltreatment Policy, Research and Training (P50HD096719), and extend existing partnerships with community stakeholders in St. Louis, Missouri. The PI will receive training in 1) performing policy evaluations with rigorous causal inference methodologies; 2) managing and analyzing large-scale ecological data; 3) conducting community-based participatory research; 4) developing NIH grants and disseminating research evidence for CAN prevention. This K01 award will enable the PI to conduct independent, community-engaged, and policy-relevant research informing states’ selection and implementation of policies to prevent CAN.

Funder: National Institutes of Health 

Amount: $664,155 

PI: Liwei Zhang, School of Social Work 

Northern bobwhite (Colinus virginianus) populations continue to decline across most of the species’ range. Many states have used conservation triage approaches to identify areas where conservation actions are likely to be effective versus areas likely to never experience population recovery. The Missouri Department of Conservation (MDC) has identified over 2.3 million acres as Quail Restoration Landscapes (QRL) to focus bobwhite conservation to “provide higher cost-share and incentive rates within quail focus areas, Grassland-focused conservation opportunity areas or on private land adjoining conservation areas (CAs).” Multiple QRLs exist in each MDC Region: four in the Northwest, Northeast, and Southwest, and three in the Southeast. One or more CAs are typically nested within each QRL and serve as a focal point for management. About 96% of the QRLs are privately owned. Bobwhite habitat management requires biannual disturbance, and unless the disturbance is a byproduct of land use, it costs money to implement. Thus, the problem faced by Missouri and many other states is how much of the land can we manage for bobwhites to achieve the desired objectives given the constraints of a limited budget and lack of ownership of 96% of the land base.

Recent research in Missouri has been conducted predominately on public land that increased understanding of how disturbances such as fire and grazing can be used to manage grassland vegetation. However, there are remaining questions as to the best way manage bobwhite populations on private working lands that will be inherently fragmented. As previously mentioned, most of the QRLs encompass mostly private land. Fall covey monitoring in the QRLs suggests that populations are typically below target densities. But, despite a lot of attention, resources committed, and biological understanding about the species the erosion continues. The final product will be a conservation planning and delivery support tool that prioritizes areas of land for bobwhite restoration that includes feasibility (i.e., can we afford it?). Priority will be a function of several parts including cost of completed proposed management practices, landowner opportunity costs, and the likelihood bobwhite populations would respond to proposed management. Additional products will include biannual updates to interested MDC staff, and private landowners (if involved in trapping and monitoring efforts), a dedicated project page on the MDC Science Sharepoint site, and relevant communications to internal and external partners as needed.

Funder: State of Missouri government 

Amount: $1,299,823 

PI: James Martin, Warnell School of Forestry and Natural Resources 

The research goals of my laboratory are focused on advancing our understanding of physiologic processes that provide the necessary flexibility to the metabolic network of prokaryotic cells. Such flexibility is needed for cells to survive challenges encountered under the diverse conditions they find themselves in, be it free-living, in association with a host as a commensal, or during the process of infection. We are particularly interested in the molecular basis of metabolism and on the physiological consequences brought about by genetic and epigenetic events that change the function of proteins either permanently or temporarily. Here we propose to define the function of two enzymes that chemically modify other proteins altering their activities. The first protein-modifying enzyme appears to target a global regulatory protein, whilst the second one appears to target an enzyme whose activity can balance the biosynthesis of building blocks with energy generation via oxidative phosphorylation. We are also continuing our work on the biosynthesis of coenzyme B12, the largest coenzyme known that is not a polymer. Specifically, we are interested in the late steps of the pathway, which occur as a multi-enzyme complex anchored in the cell membrane. Our work has advanced to the point that allows us to assemble the complex using liposome methodologies, and in so doing we can now investigate the molecular details of the assembly process. Ultimately, we will engage a microscopy expert to help us visualize what is likely to be a magnificent molecular structure. Finally, we will continue to work on a recently discovered transcription factor that we have shown modulates the expression of a large set of genes involved in iron metabolism during a Salmonella infection. We will engage a colleague working on Salmonella pathogenesis to provide insights into how genes affected by the function of this regulator impact the ability of Salmonella to establish and maintain an infection. To perform the proposed we will use innovative combinations of genetic, molecular biology, biochemical, bioinformatics and global approaches and will complement those through collaborations with spectroscopists, crystallographers, molecular biophysicists, and membrane biologists to provide comprehensive, rigorous testing of hypotheses and working models. We seek answers to questions in metabolism of microbes relevant to human health, and in so doing contribute to the mission of the NIH.

Funder: National Institutes of Health 

Amount: $3,586,538 

PI: Jorge Escalante, Franklin College of Arts and Sciences, Department of Microbiology