University Of South Dakota

NIH Research Projects · FY 2026 · 2026-06

PROJECT ABSTRACT Mesenchymal stem/stromal cells (MSCs), the most abundant adult precursor cells in the human body, have been widely explored for various experimental and clinical applications and were recently approved for clinical use by the FDA. Nevertheless, a daunting challenge remains: the poor survival and reduced regenerative capability of MSCs in hostile microenvironments in the recipient tissue markedly undermine their efficacy and treatment outcome. Our proposal, “Reinvent Mesenchymal Stem Cells - A Synthetic Biology Approach to Engineer Programmable Adult Stem Cell Theranostics,” aims to overcome these limitations by engineering a programmable cellular theranostic platform for MSCs. We previously developed synthetic genetic circuits (SGCs) having upstream genetic sensors to detect intracellular signaling and downstream secretory effector molecules to program cellular signaling and desirable cellular functions under conditions of stress or disease. Here, we propose to integrate SGCs into MSCs to engineer Autonomous Impairment-inducible MSCs (aiMSCs). aiMSCs would spontaneously detect stress- or disease-induced intracellular signals via genetic sensors and initiate transgene expression to enhance cell survival and treat targeted pathologies. To ensure the safety and translational potential of aiMSCs, we will embed two types of autonomously programmable control mechanisms: 1) dual intracellular signaling feedback controls at the sensor and effector levels, and 2) a safety switch based on endogenous microRNA binding, to respond to the microenvironment in real time and increase effector output levels when the tissue damage intensifies or turn off the SGC when the tissue heals. As proof-of-concept, we propose two specific aims to develop the aiMSC technology and explore its potential as a next-generation MSC therapy. We will use synthetic biology, genetic engineering, and computational tools to engineer: 1) murine bone marrow (BM)-derived MSCs that automatically detect and respond to inflammatory signals, augment MSC survival, and promote a destructive-to-constructive transition in tissue inflammation (aiMSC-I); and 2) human BM-MSCs (hMSCs) that detect and respond to metabolic distress- induced signals and promote hMSC survival, anti-oxidation, and mitochondrial protection (HaiMSC-M). We will use cellular, organoid, and animal disease models to validate aiMSC-I and HaiMSC-M and to demonstrate enhanced MSC survival and functioning, as well as the self-contained and self-regulated modulation of disease conditions. Large-scale genetic sensor screening and machine learning will be used to identify unique MSC- specific pathology sensors. aiMSCs represent an adaptive, self-programmed theranostic approach that augments MSCs on demand in a safe and controlled manner. aiMSCs would significantly advance patient treatment and offer new perspectives for precision medicine, designer therapeutics, and stem cell therapies.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Our overarching goal is to increase the rates of cervical cancer (CC) screening among Indigenous women in the U.S. This population experiences disproportionately high rates of cervical cancer morbidity and mortality. They are twice as likely to develop and to die from CC compared to non-Hispanic White women. They are often diagnosed at a later stage, which makes successful treatment and survival more challenging. Early detection through regular CC screening saves lives and significantly reduces human papillomavirus (HPV)- related infections, subsequent health risks, and CC mortality by up to 80%. However, approximately 45% of Indigenous women remain unscreened. To address this issue and improve CC screening rates, we aim to develop and test the efficacy and feasibility of a theory-driven, culturally-tailored, multilevel, multimedia mobile web app intervention (called wPap), specifically targeting Indigenous women in the Yankton Sioux Tribe (YST) Reservation in South Dakota. We will conduct a 2-arm randomized controlled trial using community-based participatory research and multiple methodologies over a 4-year period. We will recruit 120 YST women aged 25 to 65 years and randomly assign them to either the waitlist control group (n=60, receiving printed educational materials on CC and screening guidelines), or the wPap intervention group (n=60, receiving culturally-tailored and personalized multilevel, multimedia messages through a mobile web app). The wPap interventions will be administered for 7 days. We will conduct assessments at baseline, 1-week post- intervention, and 6-month follow-up surveys and focus groups. Aim 1 will identify individual, sociocultural, and structural determinants of CC and CC screening through qualitative assessment. The information gathered will guide developing the wPap intervention. Aim 2 will develop the multilevel, multimedia wPap intervention to promote CC screening for Indigenous women. Aim 3 will evaluate the feasibility and efficacy of the wPap intervention for increasing CC screening rates among Indigenous women. Evaluation criteria will include the intervention’s feasibility (i.e., acceptability and satisfaction) and efficacy (i.e., receipt of CC screening, changes in knowledge and attitudes/beliefs about screening, self-efficacy, and intent to undergo CC screening). By addressing barriers to screening, the wPap intervention has the potential to increase accessibility and sustainability of evidence-based preventive care, ultimately reducing health disparities in Indian Country. The results will have wide applicability, serving as a model for improving cancer-related health outcomes and early intervention for other types of cancer for Indigenous women across geographical regions and tribal communities.

NIH Research Projects · FY 2025 · 2024-05

Project Summary Colorectal cancer (CRC) has a high mortality rate due to metastasis and drug resistance. CRC cells develop metastatic characteristics by hijacking different signaling pathways to fuel tumor heterogeneity and facilitate cancer migration and invasion. Additionally, the metabolic adaptation supported by “oncogenic mitochondria” is a survival strategy developed in CRC cells. Unfortunately, the above metastatic cascade is formed and evolved during the early tumor formation and progression stages. Activation of multiple tumorigenic pathways in CRC cells leads to a poor five-year relative survival rate in patients with colon (14%) or rectal (17%) metastatic cancer. Current natural anti-cancer compounds such as camptothecin and vinblastine have a successful clinical profile. However, both camptothecin and vinblastine interfere with cell division, resulting in unwanted effects on normal cells. We have discovered that a natural plant-based anti-cancer molecule (veratridine [VTD]) induces the expression of UBXN2A protein in CRC cells. UBXN2A’s ubiquitin-like activity suppresses the mTORC2-Rictor pathway and mitochondrial mortalin, two critical tumorigenic players in CRC. This project aims to develop “smart” nanoparticles (NPs) to selectively release VTD at tumor sites at high local concentrations while leaving normal cells minimally exposed to the drug below its toxic concentrations. Our in vitro and animal experiments have demonstrated the anti-growth and anti-metastatic effects of VTD at the cellular level and have aided in elucidating its mechanisms. The proposed study will investigate the anti-growth and anti-metastatic mechanisms of VTD delivered by casein-coated NPs in patient CRC-derived organoids (PDOs) (Aim 1). A CRC metastatic mouse model with liver tumors will confirm the anti-metastatic mechanisms of NPs-VTD (Aim 2). Our central hypothesis is that casein-coated nanoparticles loaded with VTD (NPs-VTD) suppress the overdriven mTORC2 pathway and interfere with the oncogenic mitochondria in CRC cells. Human tissues and a human-like mouse model of metastatic CRC used in this study will open a platform for developing new therapeutic strategies in CRC, particularly its metastatic forms.

NIH Research Projects · FY 2025 · 2022-12

PROJECT SUMMARY Although combination antiretroviral therapy (ART) has led to significant HIV suppression and improvement in immune function, persistent viral reservoirs remain that are refractory to intensified antiviral therapy. However, ART poses many challenges such as adherence to drug regimens, the emergence of resistant virus, and cumulative toxicity as a result of long-term therapy. Moreover, these viral reservoirs directly or indirectly contribute to the rapid viral rebound that typically occurs within 2 weeks after cessation of ART. Thus, lifelong ART is required for continued viral suppression. Therefore, we need an effective approach that will eliminate HIV from viral reservoirs in individuals on suppressive ART. A number of novel far-reaching and varied therapeutic options are currently under investigation to address this concern, the most common of which is to eliminate the persistent CD4+ T cell viral reservoir. However, although latently infected CD4+ T cells are the predominant HIV reservoir, other cell types, such as macrophages and microglia also serve as sites of HIV persistence. These long-lived cells are resistance to the cytopathic effects of HIV and support persistent permissive HIV infection in the absence of CD4+ T cells. Moreover, they are resistant to CD8+ T cell-mediated killing. Therefore, we need an effective approach that will also eliminate HIV from these viral reservoirs in individuals on suppressive ART. However, in order to do this, it is essential that we understand how macrophage and microglia resist viral cytopathogenesis. Our preliminary data show that macrophages, in response to productive HIV infection, upregulate the expression of inhibitor of apoptosis proteins (IAPs) and triggering receptor expressed on myeloid cells-1 (TREM1), and that silencing or inhibition of these proteins promotes the selective death of HIV-infected cells without increasing viral replication. This suggests that (i) IAPs and TREM1 are responsible for myeloid cell resistance to HIV cytopathogenesis; and (ii) IAPs and TREM1 represent novel targets for the elimination of HIV. We therefore propose an innovative research program to: (i) conduct detailed mechanistic studies aimed at understanding how HIV-infected microglia resist viral cytopathogenesis with a focus on IAPs and TREM1; and (ii) identify new drug candidates that capitalize on these findings to reverse resistance and induce apoptosis of HIV- infected microglia without killing uninfected microglia. These studies are thus aimed at finding new effective approaches to curing HIV infection by eliminating persistent HIV infection from the myeloid reservoirs in ART- treated patients. This approach is fundamentally different from traditional strategies that target the virus itself, and we expect it to be complementary with ART. We also expect that the results from this work can be translated quickly into interventions aimed at eradicating HIV infection.

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY Alzheimer’s disease (AD) is the most common cause of dementia that affects million people and poses a serious financial burden to the nation. However, to develop effective therapeutics for AD has been a challenge. To date, no effective treatment is available to either prevent the disease or halt its progression. A major hurdle for this is the lack of reliable therapeutic targets for the disease. AD is associated with accumulation of misfolded proteins including senile (Aβ) plaques and neurofibrillary tangles. It remains unclear how these protein accumulations occur and what roles they play in the pathogenesis of AD. Additionally, AD is a multifactorial disease exhibiting symptoms both in the brain and heart. However, the temporal relationship between the peripheral symptoms to AD pathogenesis remains unknown. In response to the NOT-AG-18-051 from the National Institute on Aging, we propose to study the role of a key phosphoregulation of the proteasome in aging and AD. Specifically, we will determine whether changes in proteasome functionality, through increase or decrease of Rpn6 phosphorylation at the serine-14 residue (Ser14-Rpn6 phosphorylation), alter aging process and AD pathogenesis in both the brain and heart. Two unique mouse knock-in models, phosphorylation mimicry and phosphorylation blockade at Ser14-Rpn6, will be studied at baseline and when crossed with an AD mouse model to generate the phosphorylation mimicry-AD and phosphorylation blockade- AD mice. Furthermore, the contribution of proteasome activation by PKA to the therapeutic benefits to the brain and heart of AD animals exerted by a pharmacological strategy that can augment cAMP/PKA signaling and increase Ser14-Rpn6 phosphorylation and proteasome activities in both the brain and heart will be determined. This work will lead to significant mechanistic insight into a key phosphoregulation of the proteasome in protection against aging and AD. Success of this work can also advance the mechanistic understanding of a clinically translatable therapeutic strategy for the disease.

NIH Research Projects · FY 2025 · 2020-09

Ischemic heart disease (IHD), including acute and chronic myocardial ischemia, heart attack or acute myocardial infarction (AMI), chronic MI, and other chronic coronary disease, is the most common cause of heart failure (HF) in the US, afflicting the life of millions of Americans. Despite recent advances in the intervention of IHD, the morbidity and mortality of IHD is still high; thus, a better understanding of the molecular mechanisms by which IHD progresses to HF will facilitate the search for new measures to prevent or more effectively delay the progression of IHD to HF. Targeted degradation of most cellular proteins, normal or misfolded, is primarily performed by the ubiquitin-proteasome system (UPS) where the proteasome is a molecular machine to degrade proteins purposely tagged with a chain of ubiquitin. Proteasome malfunction and resultant accumulation of the abnormal or garbage proteins in heart muscle cells are implicated in the progression from IHD to HF; thus, improving cardiac proteasome functioning to expedite the removal of garbage proteins from heart muscle cells after heart attack is conceivably an attractive therapeutic strategy. However, deployment of such a strategy is hindered currently by the lack of pharmacological means. To this end, understanding of how proteasome function is regulated or dysregulated in IHD and what role the (dys)regulation plays in IHD are crucial. The long-term goal of this project is to exploit proteasome regulation for developing new therapeutic strategies. This proposal aims to determine the role of the emerging phosphoregulation of the proteasome by protein kinase A (PKA) in AMI, ischemia/reperfusion injury (IRI), and post-MI maladaptive cardiac remodeling and HF progression. In the last cycle, we have established first in animals that the proteasome subunit RPN6/PSMD11 can be specifically phosphorylated at Ser14 by PKA, resulting in marked increases in proteasome proteolytic function, taking advantage of our newly created gene- edited mice where the phosphorylation of Rpn6 at Ser14 (pS14-Rpn6) is genetically blocked or mimicked. We have now detected remarkable alterations in pS14-RPN6 and total RPN6 proteins in explanted failing human hearts and mouse MI models and striking mitigation of AMI progression by genetic intervention of pS14-RPN6 in mice. Hence, we propose to use genetic approaches to unequivocally establish the mechanistic role of these alterations in AMI, IRI, and chronic post-MI remodeling and HF. This will advance our understanding of IHD pathophysiology and provide genetic demonstration that targeted activation of the proteasome via, for example, compartmental stimulation of PKA could be a new treatment strategy for IHD.

NIH Research Projects · FY 2025 · 2016-02

The progress in understanding how neuronal dysfunction can lead to nervous system disorders has drawn attention to the central role played by trophic factors in modulating brain function. Cognitive deficits, which are widely prevalent in neuropsychiatric disorders, are known to be regulated by trophic factors. The hippocampal actions of neurotrophic factors have been shown to be particularly important, influencing cellular pathways and mechanisms to produce behavioral effects. Erythropoietin (EPO), a naturally occurring hormone and trophic factor, widely prescribed to treat anemia, exerts robust neurotrophic actions in the brain. Moreover, peripheral administration is sufficient to elicit CNS effects in several preclinical and clinical psychiatry studies. Multiple human studies have demonstrated that EPO produces cognitive enhancing effects. The regulation of behavior is considered to be a result of neurotrophic activity that is independent of EPO’s physiological and hemostatic role in regulating hematopoiesis. However, the specific trophic mechanisms in the brain have not been characterized. Furthermore, the use of an inherently erythropoietic molecule to produce therapeutic neurotrophic effects can lead to elevated blood viscosity and increase the risk for adverse vascular events. We therefore utilize chemically engineered EPO derivatives that are non-erythropoietic but retain neurotrophic activity, to investigate the role of its hippocampal actions in cognition. Employing a combination of conditional, region-specific, receptor knockout mice and viral-mediated gene manipulation we will determine the role of hippocampal neurotrophic factor-driven mechanisms at the molecular, cellular and behavioral levels. Our studies are expected to provide new insight into trophic factor-mediated modulation of cognitive behavior and also inform the development of novel trophic factor based therapeutic agents.

NIH Research Projects · FY 2026 · 2013-06

Project Summary. The opportunity for undergraduates to conduct research is critical for developing a rigorous program in biomedical education. Specifically, it provides an experience not normally part of lecture- or laboratory-based coursework and prepares students for post-graduate training or careers in basic research or clinical disciplines. However, opportunities for undergraduate biomedical research experiences are not uniformly available across the United States, with both students at institutions with developing research capacity, including those in EPSCoR and IDeA states, and students from primarily rural areas being especially underserved. Many of these undergraduates attend institutions with less extramural support for biomedical research than institutions in more populous states. The SPURA program at the University of South Dakota (USD) was developed in 2014 with support from NIDA to address these gaps and is seeking renewal to continue providing research opportunities. The specific aims are: 1. To expand undergraduate research opportunities for students in South Dakota and surrounding states, emphasizing quality training of students from first-generation, rural, and other backgrounds aligned with USD’s mission. 2. To encourage more South Dakotan students to participate in research and ultimately pursue post-graduate research careers and/or training in substance use and related mental health issues. 3. Advance the field of substance use and related mental health disorders by providing students with multi-disciplinary training through seminars and learning opportunities, exposing them to a range of research disciplines that address substance use, rather than focusing solely on a single discipline. Each summer, this program will enroll eight students in a multi-disciplinary research experience aimed at providing students with an opportunity to conduct mentored, open-ended studies in fields related to substance use and underlying mental health. The program will incorporate a wide range of experimental approaches, including human subjects, preclinical studies, population health research, and translational research. Faculty involved in this program will include members of the Departments of Biology and Psychology (both part of the School of Arts and Sciences), the Sanford School of Medicine, Beacom School of Business, and the School of Health Sciences. The SPURA program has been highly successful, having supported 78 students, most from first-generation and/or rural backgrounds. Moreover, approximately 80% of alumni subsequently enroll in research- or professional health-based post-graduate education programs. Finally, long-term interactions with alumni indicate that the program had a positive impact on their sustained interest in research and their efforts to improve patient care for those with substance use disorders.

NIH Research Projects · FY 2025 · 2001-09

SD INBRE Project Summary The South Dakota IDeA Network of Biomedical Research Excellence (SD INBRE) is hosted by the Sanford School of Medicine of the University of South Dakota (USD), in Vermillion, SD. This is the SD component of the INBRE program, and it has been funded by the NIH/NIGMS since 2001. The goal of SD INBRE is to maintain and grow the biomedical research infrastructure within the state of South Dakota. To accomplish this, we will expand research capacity in SD in the area of cell biology and the control of cell and microbial growth. Cell biology is broadly defined for the purposes of SD INBRE, and our students and faculty will evaluate the molecular interactions that both influence a cellular response and are produced after a cell is stimulated. We will align core resources to increase the use of equipment, personnel, funding opportunities, and reporting infrastructure as we maximize research productivity across SD INBRE. Our plans to enhance SD INBRE faculty development in scholarship, grantsmanship, and mentorship will allow faculty at partner institutions to gain research support and mentoring as they increase publications and grant submissions. We will provide research opportunities for SD INBRE undergraduate students to receive training in biomedical sciences at partner institutions throughout SD. These research experiences will include both summer and academic year opportunities. Our plans for outreach include providing K-20 students with examples of how biomedical research can help them achieve their career goals. We will use our small population of scientists to engage researchers across all career stages at our partner institutions. Together, we will accomplish our goal by providing SD students and faculty with a unique infrastructure that will advance biomedical research across our state. Over the past two decades, SD INBRE has established a culture of biomedical research across South Dakota. The core resources and research opportunities have expanded training and mentoring of students and faculty across our network. We will build on these successes as we use our unique infrastructure to align faculty, equipment, and personnel across SD INBRE.