Author: orandall

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 

As the U.S. Army Corps of Engineers Engineer Research and Development Center (ERDC) continues to bolster the development and deployment of nature-based infrastructure solutions, the Institute for Resilient Infrastructure Systems (IRIS) at the University of Georgia proposes to expand its capacity to conduct applied research in conjunction with a broader set of installations and enhance its research operations to address issues identified through this partner engagement. This work will further the shared mission of ERDC and IRIS to work with military installations and adjacent communities to build stronger, more resilient military and civilian communities better capable of fulfilling the military’s mission through the use of Engineering With Nature® (EWN). EWN focuses on using nature-based solutions (NBS) to fulfill engineering objectives such as reducing flood and erosion damages, protecting critical infrastructure, promoting navigation, and securing safe and ample water supplies. The natural systems utilized within NBS include river floodplains, forested water supply watersheds, freshwater and coastal wetlands, dunes and beach systems, living shorelines and reef structures, among other elements. These systems may be used independently, or in conjunction with more traditional infrastructure elements such as dams, sea walls, or levees. Using NBS can often more equitably and effectively provide infrastructure services compared to traditional systems, while also providing additional social, ecological, and community benefits. EWN is advancing the use of NBS by catalyzing technical scientific and engineering advances in conjunction with other fields, including environmental science, ecology, and the social sciences, to develop a collaborative, equitable, and cost-effective approach to infrastructure planning, design, and implementation. The U.S. Army Corps of Engineers Engineer Research and Development Center (ERDC) continues to advance EWN principles with cutting edge research, education, and training through the creation of the Network for Engineering With Nature (N-EWN) jointly with IRIS. Recognizing this demand for additional research and data to promote resilience through EWN, IRIS proposes to expand its work both geographically and in the scope of services it provides. Building on its innovative and novel engagement strategies, IRIS will expand the number of installations that participate in the network to develop applied research questions that address their specific resilience needs, create and fund training programs in collaboration with ERDC for installation planners and engineers to learn to utilize the results of this research to further principles of EWN and resilient design and to inform local military and civilian resilience planning and infrastructure design.

Funder: U.S. Department of Army 

Amount: $5,484,643 

PI: Brian Bledsoe, College of Engineering 

Despite significant advancements in our knowledge of marine microbial ecology over the past few decades, gaps remain in our understanding of microeukaryote diversity and physiology across vast regions of the open ocean, and how they contribute to community ecology and biogeochemistry. In an effort to address this, we combined omic and physicochemical measurements across a ~4,600 km section of the central Pacific Ocean, traversing oligotrophic gyres and the equatorial upwelling zone. A surprising finding was the relative abundance of dinoflagellates in these offshore communities, which are commonly observed in coastal settings but less understood in the open ocean. They were detected throughout the surface and mesopelagic, with distinct functional profiles between depth zones. Surface communities showed indications of phototrophic carbon fixation and potentially mixotrophy (both phototrophy and heterotrophy), while deep communities reflected nutrient cycling and degradation, suggesting this group is ecologically successful across a vast region of the ocean. In addition, metabolic signatures based on both dinoflagellate transcripts and proteins indicated metabolic plasticity in response to variable nitrogen and iron regimes, with ironstressed physiology in equatorial upwelling surface waters and nitrogen stress in the oligotrophic gyres. I led the data integration, performed the computational comparisons, and wrote the manuscript. This work has led to new questions I am interested in addressing, including whether surface and deep prostistan populations are taxonomically connected, how long proteins from the surface ocean can remain intact after sinking below the euphotic zone, and the ecological roles of mixotrophy in offshore environments.

Funder: Simons Foundation 

Amount: $810,000 

PI: Natalie Cohen, Franklin College of Arts and Sciences, Department of Marine Sciences 

A fundamental feature of a living system is its integrated network of biochemical pathways that respond to endogenous and environmental stresses. In humans, there is a strong connection between metabolic network dysfunction and disease, while in microbes metabolic network structure dictates organismal capabilities, including pathogenesis. Metabolic strategies are conserved across biology, and insights obtained from model organisms provide the means to advance our understanding of general metabolic paradigms, which can often be extrapolated to higher organisms including humans. The PI’s laboratory utilizes a broad approach that includes in vivo genetics, molecular biology, biochemistry, bioinformatics, proteomics, and metabolomics and other global approaches to address timely questions in metabolism. In the long-term, the PI’s research will contribute to the understanding of the structure and integration of bacterial metabolic networks, how they respond to perturbation, and how specialized capabilities (e.g., causing disease) are integrated into metabolism. Reaching this vision will require the rigorous definition of metabolic components and their integration, which together form the complex system of metabolism. Knowledge of fundamental metabolic processes and a mechanistic understanding of functional components is critical to efforts aimed at treating metabolic diseases, defining pathogenic strategies, and targeting metabolism for rational drug design, synthetic biology, microbiome research, etc. Efforts in the next five years focus on, i) extending the understanding of the RidA stress system, ii) comparing the endogenous stress systems of multiple microbes, iii) identifying functions of additional Rid protein family members, iv) integrating results from these studies into the metabolism of pyridoxal phosphate, and v) defining a function for the conserved YggS protein. Notably, the human YggS homolog (i.e., PROSC) is a biomarker in B6 epilepsy in humans. The goals of this proposal will be accomplished through a combination of chemical, biochemical, molecular genetics, bioinformatics and global approaches. The work here is motivated by our desire to understand the complex system of metabolism, specifically understanding metabolic stress generated by the production of reactive metabolites during growth, how such stress can damage cellular components if not neutralized and discovering a unifying role for the members of the broadly conserved Rid protein superfamily family.

Funder: National Institutes of Health 

Amount: $1,762,429 

PI: Diana Downs, Franklin College of Arts and Sciences, Department of Microbiology 

This award supports the research training of postdoctoral researchers, PhD students and undergraduates in the mathematics department at the University of Georgia working in three closely related geometric areas: algebraic geometry, symplectic geometry and low-dimensional topology. These fields deal with both foundational questions at the heart of pure mathematics, such as understanding the possible shapes of spaces and their descriptions in terms of equations, and questions related to mathematical physics, computation and new ideas for analysis of large data. The training includes collaborative seminars, outreach and visualization projects, summer schools, visiting speakers, and research working groups. 
 
This RTG award supports students and postdocs working under the supervision of eight topologists, algebraic geometers and symplectic geometers at the University of Georgia (UGA). The topologists all work on problems that have strong connections with symplectic and contact topology, the algebraic geometers study moduli spaces that have fascinating topology and can be studied using symplectic techniques, with connections to mirror symmetry and mathematical physics, while the symplectic geometry work extends all the way to connections with topological data analysis. In addition to special seminars, workshops, RTG bridge-building topics courses, research working groups, and computational working groups, this project supports several innovative outreach and recruitment-oriented activities. These include the Geometry Research, Outreach and Visualization Initiative, in collaboration with Moon Jang, UGA associate professor of graphic design, and with interdisciplinary project management provided by the UGA Arts Collaborative, which involves participants from multiple levels working together on visual communication projects directly related to this RTG’s research activities. 

Funder: National Science Foundation 

Amount: $2,497,014 

PI: David Gay, Franklin College of Arts and Sciences, Department of Mathematics 

Vascular and lymphatic systems have emerged as attractive therapeutic targets in a variety of diseases. Stimulating angiogenesis accelerates wound healing and tissue regeneration after myocardial infarction whereas inhibition of angiogenesis suppresses tumor growth1 and progression of intraocular neovascular diseases. Likewise, stimulating lymphangiogenesis aids in the treatment of secondary lymphedema, prevents atherosclerosis and could promote cancer immunotherapy. Endothelial cells (ECs) are key components of arterial, venous, and lymphatic vasculatures. Studies in mice identified the transcription factor NR2F2, also known as COUP-TFII, as the key regulator of EC fate. However, major gaps exist in our knowledge of the cellular and molecular mechanisms by which NR2F2 regulates EC specification. Which EC subsets, developmental transitions and molecular networks are targeted by NR2F2 is unknown. NR2F2 and its homolog NR2F1 are members of the nuclear hormone receptor (NHR) family of transcription factors. NHR activities are controlled by small molecules derived from endogenous metabolism or diet. Recently, we identified 1-deoxysphingosines as natural ligands for NR2F1/2. Although 1-deoxysphingosines have been detected in tissues, no physiological roles have yet been proposed for these metabolites – they are considered toxic byproducts of sphingolipid biosynthesis resulting from mutations in subunits of the SPT complex. Our study is the first to suggest that these metabolites have a physiological function as regulators of NR2F1/2-mediated transcription. The mechanistic understanding of how NR2F1/2:1-deoxysphingosine axis regulates EC development would yield knowledge needed to modulate blood/lymphatic vessel development in research and clinical settings. In this proposal, we will (1) define the cellular and molecular networks regulated by NR2F1/2 and its ligand, 1-deoxysphingosine, during arterial venous, and lymphatic specification of hESCs, (2) delineate molecular pathways that modulate 1- deoxysphingosine synthesis and uptake and identify major physiological sources of this metabolites in vivo, and (3) define the structure of ligand-bound NR2F2 LBD and validate ligand-receptor interactions. The work proposed is significant because it will identify molecular pathways that modulate NR2F2 transcriptional activity thus contributing to an understanding how NR2F2-mediated transcriptional networks regulate development and physiology of vascular and lymphatic systems. This knowledge will be instrumental for developing ligand analogs that can act as chemical modulators of NR2F2 activity under normal and disease conditions. Our approach is innovative because we will develop new concepts and methodologies that could be adapted to understand the molecular bases of NHR-mediated transcription and to search for ligands of other orphan NHRs.

Funder: National Institutes of Health 

Amount: $3,557,347 

PI: Natalia Ivanova, Franklin College of Arts and Sciences, Department of Biochemistry and Molecular Biology 

Dynamic uterine fluid volume is essential for successful early pregnancy. Uterine fluid volume is the net result of secretion and absorption, which are respectively promoted by ovarian estradiol (E2) and progesterone (P4) through the uterine epithelium. Dysregulated uterine fluid movement has been associated with impaired early pregnancy, particularly in women with endometriosis undergoing ovarian stimulation for in vitro fertilization-embryo transfer (IVF-ET) who often experience uterine fluid retention and implantation failure. Na+ and Cl- are the dominant ions in the uterine fluid. Amiloride-sensitive epithelial Na+ channel (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR) have been implicated in their movements across the uterine epithelial cell membrane to generate osmotic gradients for facilitating fluid movement through the epithelial membrane water channels, aquaporins (AQPs). Despite the essential roles of sex hormones and ion/water channels in regulating dynamic uterine fluid movement during early pregnancy, the precise hormonal and ionic mechanisms remains elusive. Our preliminary data in mouse models revealed inhibition of uterine fluid absorption by amiloride on day 0.5 post-coitus (D0.5) but not D3.5, dynamic expression of genes for ion/water channels in D0.5 and D3.5 luminal epithelium (embryo implantation initiates ~D4.0 in mice) by mRNA-seq, and a novel function of E2-estrogen receptor α (ERα) in regulating uterine fluid absorption. In human models, we developed a microphysiological system that enables a microfluidic co-culture of ovarian follicles and human endometrial (Endo) organoids for engineering a female reproductive tract-on-a-chip (FRT-Chip), and our preliminary data showed the longterm survival and 3D architecture of Endo organoids in vitro as well as the regulation of ENaC and CFTR by cocultured follicles. Herein, we formulate our central hypothesis that ERα and PR converge on hormonal and ionic mechanisms to finely coordinate temporal uterine fluid absorption during early pregnancy, while dysregulation of ion/water channels in eutopic endometriosis endometrium or under ovarian stimulation for IVF leads to disrupted uterine fluid dynamics and impaired early pregnancy. There are two Specific Aims. In Aim 1, we will use transgenic mouse models with ERα or PR deficiency in the uterine epithelium to determine in vivo functions and regulatory mechanisms of selected Na+ channels, Cl- channels, and water channels in the uterine epithelium for uterine fluid absorption during early pregnancy. In Aim 2, we will collect normal and endometriosis endometrium biopsies from menstruating women and IVF-ET patients to compare ion/water channels in human endometrium biopsies and perform a microfluidic co-culture of follicles and Endo organoids to engineer an FRT-Chip and investigate mechanisms regulating human uterine fluid movement under physiological and pathological conditions. The successful completion of these studies will generate a comprehensive molecular atlas of uterine fluid movement. Identification of local uterine epithelial factors is a crucial first step for developing treatments to regulate uterine fluid movement, improve embryo implantation success, and reduce early pregnancy loss. 

Funder: National Institutes of Health 

Amount: $3,910,102 

PI: Xiaoqin Ye, College of Veterinary Medicine