2020 Pilot Grant Recipients
Department of Neurosurgery, UNMC
Evaluation of Changes in Brain Connectivity After Tumor Resection
For a patient with a brain tumor, the idea of performing surgery on their brain cultivates a sense of fear and doom prompting the question “How will this affect who I am?” Brain tumor patients can suffer from cognitive and neurologic changes as a result of their treatment and disease. Unfortunately, due to a lack of scientific understanding, these changes in brain functioning are often difficult to predict. Brain function can be assessed with special imaging techniques to look at connections throughout the brain called connectivity. There is structural and functional connectivity that can be assessed. We predict that brain connectivity changes that occur after a tumor is removed will correlate to cognitive and neurologic changes. Surgery is the primary treatment for most brain tumors and understanding how brain connectivity and cognitive outcomes are related and how they are affected by this treatment will determine neurologic prognosis and impact treatment decisions. This is important because neurologic status is correlated to survival in brain tumor patients. The goal of this project is to visualize and quantify changes in the brain of patients undergoing brain tumor surgery through high-quality, high-resolution structural and functional brain imaging and brain connectivity measures. We will accomplish this by pursuing the following specific aims: AIM 1 will assess the brain structural and functional connectivity changes that occur after a tumor is removed from the brain and determine if it is correlated to cognitive and neurologic changes in the patient. AIM 2 will examine the effects of tumor location, tumor size, tumor type, patient age, and sex on brain connectivity changes. Ultimately, the knowledge gained by this study will better inform doctors and patients about how surgery may affect their brain functioning, which could result in improved quality-of-life as well as provide valuable insight into brain organization and re-organization. How surgery affects brain networks and neurocognitive status is important as this information can translate into improved predictions of neurologic prognosis after surgery and safer treatment choices.
Department of Surgery,
Division of Vascular Surgery, UNMC
Identification of biomarkers for abdominal aortic aneurysms
Abdominal aortic aneurysm (AAA) is a complex inflammatory disease that results in progressive dilation of the aorta to the point of rupture. At present, AAA is one of the few cardiovascular diseases for which there is no pharmacological therapy. Since most AAA are detected at a small size (less than 5 cm), regular checkups and routine surveillance imaging are essential for evaluating the growth of the aortic diameter. Aortic growth is variable and patient-dependent. Usually, the aortic dilation is observed for years prior to surgical intervention. Therefore, there is an imminent need for identifying biomarkers to predict aortic growth and developing a medical therapy to inhibit aneurysm expansion. The ultimate goal is identification of biomarkers that predict more rapid growth of AAA. Through a collaboration with ThermoFisher Scientific, we are in the process of measuring 500 putative biomarkers. This information will have important clinical relevance regarding 1) follow-up intervals for imaging and 2) estimating timing of future repair. Future clinical trials of medical therapy could use these as early markers of treatment efficacy.
Nutrition and Health Sciences, UNL
Nebraska Center for the Prevention of Obesity Diseases, UNL
AI-Powered Monitoring of Focused-Activity and Just-in-Time Intervention for Weight Management
With a mission to counter the obesity and diabetes epidemic and promote healthy living in high-risk populations, this proposal aims to create an efficient smartphone-based automatic system that interacts with users to accurately assess dietary intake and energy balance, identify unhealthy lifestyle habits, make personized recommendations, and deliver just-in-time interventions for users to take immediate actions. By including investigators with demonstrated expertise in health informatics, machine learning, software developing, nutrition, obesity and metabolic disease prevention, and research methodology and collaborating with clinicians (e.g., Registered Dietitian, Certified Diabetes Educator) and healthcare facilities (Center for Diabetes and Nutritional Health of Methodist Hospital, Omaha, NE), we propose to develop and pilot test a novel smart health mobile system leveraging digital information in health management and obesity and metabolic disease prevention with the following main specific aims: 1) develop a novel smart health system leveraging digital health information to monitor real-time energy balance and deliver just-in-time intervention for weight management; and 2) conduct a proof-of-concept study to pilot test the novel system. Successful outcomes of our project will transform the conventional personal health management process and advance the knowledge and practice of digital patient-centered healthcare for obesity treatment and prevention. We anticipate this novel system will benefit high-risk populations particularly those with limited access to structured health education and intervention programs and health-care facilities such as people living in rural regions once this system is fully developed and tested.
College of Nursing, UNMC
A Mouse Model of Cancer-Related Fatigue
Cancer-related fatigue (CRF) is a dominant symptom for men with prostate cancer related to the cancer and its treatment. CRF often contributes to enhanced cancer morbidity, negatively interferes with treatment adherence and efficacy, and worsens health-related quality of life. There are no specific treatments for CRF, attributed to a lack of knowledge of the biologic mechanisms contributing to this pathology. CRF is often described by cancer patients as a lack of energy, tiredness not relieved by rest, or an inability to complete tasks. These physical descriptors suggest that mitochondrial impairment and metabolic dysfunction could contribute to CRF. However, few studies have investigated the metabolic mechanisms of CRF. We will test our central hypothesis that metabolic mechanisms drive the pathobiology of CRF. In Specific Aim 1, we will determine the metabolic profile of fatigue in a preclinical model of CRF. Comprehensive assessment of metabolic parameters combined with fatigue severity will allow us to identify specific tissues and parameters that may underlie CRF for future therapeutic targeting. In Specific Aim 2, we will determine the mechanistic role of mitochondrial superoxide to CRF. The proposed study will be the first to determine a metabolic profile for CRF using a prostate cancer mouse model. A mouse model is instrumental for controlled and standardized mechanistic studies of CRF, addressing many of the limitations of prior clinical research. Findings from this study will identify targets for future tissue-specific mechanistic investigation, foster hypotheses for validation in clinical samples, and eventually lead to the identification of mechanism-based interventions, with the goal of improving quality of life for those with CRF.
Department of Neurological Sciences, UNMC
Patterns Activity and Cognition During Treatment (PACT): A Pilot Smartphone Intervention in Women Receiving Chemotherapy for Breast Cancer
Up to 75% of breast cancer survivors (BCS) report cognitive declines during treatment, and over 45% experience clinically significant cognitive decline pre- to post-chemotherapy. The proposed study represents the first step toward our long-term objectives of establishing the effectiveness of novel daily physical activity (PA) profiles for improving cognitive function in BCS; and disseminating our innovative, technology-delivered approach for the promotion of PA behaviors in survivor populations with limited access to cancer rehabilitation resources (e.g., rural patients). The specific aims are: (1) Test the feasibility and acceptability of a smartphone- delivered intervention targeting daily non-exercise PA and/or structured exercise in 24 women receiving adjuvant chemotherapy for breast cancer; and (2) Estimate effect sizes associated with the intervention components delivered alone or in combination on cognitive function at post-intervention. Data will be used to inform the design of a larger, externally-funded randomized exercise trial. Our protocol addresses canonical PA recommendations, in addition to novel recommendations based upon emerging evidence of the health risks of prolonged sitting and health benefits of frequent daily movement. Findings will provide important information that, long-term, may be applied to cancer populations with fewer healthcare resources and may lead to enhanced clinical recommendations for PA during cancer treatment.
Department of Internal Medicine,
Division of Nephrology, UNMC
Predictors of Clinically Significant Kidney Function Decline in Patients Receiving Long-Term Left Ventricular Assist Device (LVAD) Support
Over 2,500 LVADs are implanted each year in the US and 30% of these are in the Midwest. Kidney dysfunction is very common in patients on LVAD support and leads to higher mortality. GP IDeA-CTR institutions comprise the census region that has the highest rates of LVAD-induced kidney dysfunction and in-hospital mortality in the entire country. Reasons for this disparity are unknown. Further, contributors to LVAD-induced kidney dysfunction remain poorly understood. If modifiable predictors for kidney dysfunction among potential LVAD recipients remain undetermined, then the region containing GP IDeA-CTR institutions will likely continue to see disproportionately high mortality rates in this rapidly growing population. The purpose of this study is to leverage a nationwide registry of over 25,000 patients to identify determinants for the incidence of chronic kidney disease (CKD) and CKD progression in patients receiving long-term LVAD support. Identification of determinants for LVAD-induced CKD would reveal potential targets for intervention to reduce rates of kidney dysfunction and ultimately mortality among patients on LVAD support. Over time, we will be able to 1) systematically and efficiently discern the causal pathway of LVAD-induced kidney dysfunction and 2) further individualize informed consent for potential LVAD recipients.
Department of Pharmaceutical Sciences,
College of Pharmacy, UNMC
Development of NTSR1-targeted Radiotherapeutics for Colorectal and Pancreatic Cancers
Currently, there are no effective, curative therapeutic options for metastatic colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). Therefore, new therapeutic approaches are desperately needed to combat these deadly diseases. Targeted radionuclide therapy (TRT), which targets tumor-specific biomarkers, has been one approach in the pursuit of effective CRC and PDAC therapeutics. The development of low molecular weight TRT agents is particularly attractive due to their rapid targeting and non-target clearance properties. However, for many investigated low-molecular-weight TRT agents, the short residence time in tumors due to inherently high clearance rates of the agents and their metabolites inhibits therapeutic efficacy and clinical translation. The purpose of this study is to design a TRT that targets the neurotensin receptor subtype 1 (NTSR1), a receptor found to be overexpressed in large segments of the CRC and PDAC patient population. Compared to other radiotherapy approaches, targeted radionuclide therapeutics (TRT) allows for the selective delivery of therapeutic radiation doses to tumors, while at the same time reducing non-target toxicities. With this project, we seek, for the first time, to explore utilization of irreversible, protease inhibitors to increase the tumor-residualiztion of TRTs for colorectal and pancreatic cancers.
Department of Internal Medicine,
Division of Cardiovascular Medicine, UNMC
Trends in Indications for Performing Left Atrial Appendage Occlusion with the WATCHMAN Device
A patent foramen ovale (PFO), connecting the upper two chambers of the heart, is present in approximately 25% of humans and can serve as a mechanism of stroke in otherwise healthy individuals. Percutaneous PFO closure has the potential to improve the health of a large population by reducing stroke risk in appropriate patients; conversely, inappropriate use carries unnecessary risks of stroke, bleeding, and infection. In addition, appropriate PFO closure can immediately improve patients’ quality of life by reassuring them that recurrent stroke is unlikely and by obviating potential treatment with lifelong anticoagulation. Furthermore, appropriate use of PFO closure reduces healthcare costs by preventing the need for expensive stroke care or anticoagulation management, while inappropriate use entails unnecessary procedural expenses. Inappropriate PFO closure based upon the false premise of migraine treatment is an ineffective use that may be common. The purpose of this study is to characterize current real-world utilization of PFO closure using US administrative claims data. As a primary outcome, we will determine trends in PFO closure in US adults (age >18 years) from 2006 through 2020. We hypothesize that PFO closure increased steadily over most of this time period and then much more rapidly in 2017 following the publication of major trials and the FDA’s device approval. As a secondary outcome, we will assess the indication for PFO/ASD closure. We hypothesize that a substantial and growing fraction of patients are undergoing PFO closure "off-label," without evidence of recent stroke or embolic events. As another secondary outcome, we will assess trends in patient and hospital factors associated with PFO/ASD closure. We hypothesize that many patients unlike those in the major trials are undergoing PFO closure. We further hypothesize that characteristics of not-for-profit, large, teaching hospitals in urban, affluent areas will be associated with the largest volumes and most rapid increases in PFO closure. Knowledge of trends in the use of PFO closure will guide strategies to this critical procedure is widely accessible to the appropriate patients and not performed inappropriately.
Department of Neurological Sciences,
Department of Ophthalmology, UNMC
Visual Search in Glaucoma: Relative Contributions of Vision, Cognition, and Eye Movements on Impaired Target Localization in Complex Naturalistic Sciences
Glaucoma is a blinding neurodegenerative disease diagnosed in approximately 3.5% of all adults over the age of 40, making it the second leading cause of blindness worldwide. Patients with glaucoma experience difficulty with multiple activities of daily living, including reading, mobility, and driving. Visual search, which involves coordinating visual and cognitive abilities to locate objects in our environment, is critical for nearly every activity we perform on a daily basis. Understanding why visual search is impaired in patients with glaucoma promises to inform clinical strategies for improving their activities of daily living. Our broad goal is to determine which factors contribute to impaired visual search performance in glaucoma. To achieve this goal, the current work proposes the following specific aims. (Aim 1) Evaluate visual search performance in glaucoma patients (relative to controls) across manipulations of environmental scene context and image characteristics; we hypothesize that visual search performance will be slower in patients with glaucoma when they search for targets within more naturalistic scenes with complex image characteristics relative to scenes with simple image characteristics. (Aim 2) Evaluate the impact of perceptual, neurocognitive, and eye movement patterns on visual search performance in patients with glaucoma (relative to controls); we hypothesize that visual search performance will be slower in glaucoma patients with greater peripheral visual field loss, reduced neurocognitive function, and more biased eye movements away from regions of visual field loss. Results from this study will inform the development of rehabilitation strategies, such as augmented reality technologies, so that patients are able to overcome their visual search deficits and improve their overall quality of life. This technology will be translatable to the community level, which promises to improve quality of life in patients with visual field loss in Omaha and the greater Nebraska area.
Department of Neurological Sciences, UNMC
3 Printed Scaffold to Assist Stem Cells for Ischemic Stroke Treatment
Stroke accounts for 1 of every 20 deaths in the United States. Approximately 87% of all strokes are due to ischemic injury. Ischemic stroke occurs when a cerebral vessel narrows or loses pressure, leading to a cystic cavity in the downstream tissue. Such a lesion cavity has been largely responsible for prolonged neurological deficits and permanent disability. There are no effective treatments for cerebral strokes. Stem cell transplantation may represent a promising strategy to promote tissue regeneration. However, the hostile environment created through the loss of vascular structure at the lesion site makes repair extremely difficult. This results in poor survival rate and low engraftment of these transplanted cells. Our long-term goal is to develop biomaterial-based strategies to facilitate the repair of ischemic stroke lesions through two specific aims: (1) To develop 3D-printed hydrogel scaffolds with uniaxially aligned microchannels and Reelin gradients to promote NSC migration and differentiation; (2) To determine whether our 3D-printed hydrogel scaffold promotes integration of transplanted NSCs into brain lesions in a rat ischemic stroke model. This translational proposal is expected to lead to a new treatment for ischemic stroke patients, which can be also readily applied to treat traumatic brain and spinal cord injuries.
Department of Health, Nutrition, and Exercise Sciences, NDSU
The Great Plains Internet Wellness for Aging Study: The GP I-WAS Project
Obesity is a major public health concern in older adults, who are also one of the fastest growing populations in the United States. The health consequences associated with obesity in older adulthood are severe and include increased risk for chronic diseases, poor physical functioning and early mortality. Concurrently engaging in healthy behaviors such as physical activity, a healthy diet, and adequate sleep have each shown to be influential in reducing obesity. Despite evidence suggesting that these healthy behaviors reduce the risk for obesity, older adults have difficulty achieving such healthy lifestyles due to barriers such as geographical isolation from lack of transportation, motivation and education. The internet is an effective mode for relaying health information to a wide-ranging audience, including those that live in rural communities or are homebound. Further, internet usage among older adults continues to increase. Therefore, the internet could be an effective tool for administering a wellness intervention for older adults and incorporating community-based participatory research principles such as inviting stakeholders (i.e., older adults) in all phases of the research will magnify the impact of the research for the population in which it is intended to help. Our long-term goal is to help older adults achieve healthy lifestyles that promote successful aging. The overall objective of the proposed research, which is the next step in pursuit of that goal, is to improve healthy lifestyles in older adults by utilizing the internet for delivering a wellness intervention that is designed by both investigators and stakeholders. To propel toward accomplishing our overall objective, the following three specific aims will be pursued: 1) collaborate with stakeholders in all phases of the internet-based wellness intervention to gain knowledge on the perspectives of the older adult population, 2) assess the feasibility of an internet-based wellness intervention for obese older adults, and 3) determine if completing an internet-based wellness intervention improves healthy behaviors among obese older adults. We will recruit 20 eligible older adults to participate in an internet-based wellness intervention.
Department of Cellular and Integrative Physiology, UNMC
Targeted Delivery of H2S to Mitigate Cell Death in Obesity/Diabetes-Induced Cardiomyopathy
Diabetes induces death of cardiomyocytes that instigates adverse cardiac remodeling leading to heart failure. Reduced cardioprotective hydrogen sulfide (H2S) is associated with cardiac remodeling in diabetes. How reduced H2S induces death of cardiomyocytes in diabetes remains unclear. H2S donor therapy has cardioprotective effects in preclinical studies. However, a major therapeutic challenge is targeted delivery of H2S gas to the heart. In this proposal, we will develop a non-invasive and safe approach for targeted delivery of H2S gas into the diabetic heart. We will investigate the molecular mechanism by which H2S donor mitigates death of cardiomyocytes and ameliorates cardiac dysfunction in diabetes.
Department of Pediatrics, USD
Injury Rates and Physical Activity in Youth Football: Tackle vs. Flag
Physical inactivity-related diseases and conditions present a major health challenge to the US population and the underlying behaviors that contribute to these poor health outcomes are often established in childhood. Organized sports provide opportunities to encourage physical activity and promote healthy behaviors among youth. The importance of sports as a strategic priority for improving our nation’s health was recently highlighted by the development of a National Youth Sports Strategy by the US Department of Health and Human Services. Tackle football is one of the most popular sports in the US, played by more than two million children younger than high school age and approximately one million high school athletes. While all sports have inherent risks of injury that should be factored into decisions of whether or not to participate, emerging research on brain injury risk in tackle football has elicited important questions about the safety of this sport, particularly for children and adolescents. Although evidence-based information on brain injury risk in youth football is limited, there is growing concern that participation in this sport puts players at an unacceptable risk for both acute and chronic brain injury, much of which can be attributed to tackling. Thus, flag football has increasingly been promoted in recent years as an alternative to tackle football, based largely on the assumptions that flag football is safer and that its players benefit from being more physically active than tackle players. However, existing research comparing injury rates and physical activity in youth tackle and flag football is sparse. We will address these knowledge gaps by a) comparing injury rates of tackle and flag football players in the same community youth football program (Aim 1), and b) comparing physical activity performed by youth tackle and flag football players throughout one season (Aim 2). Ultimately, knowledge gained from this research will offer valuable new evidence that can guide public health recommendations aimed at minimizing risks and maximizing benefits of youth football participation. Furthermore, this information will empower parents and youth football players to make educated decisions about their own participation in this sport.
Department of Oral Biology,
College of Dentistry, UNMC
Greatwall Kinase as a New Therapeutic Target foe Triple-Negative Breast Cancer
Cancer progression relies on continuous, and dysregulated cell cycle progression; cancer resistance to radiation and DNA damaging drugs is stemmed from the tumor cell's ability to resume cell proliferation under these treatment conditions. Thus, pathways mediating cell cycle progression and DNA damage responses hold a key to the better understanding of cancer progression and resistance, and the development of the next paradigm of anti-cancer therapeutics. In this project we focus on an enzyme that governs both cell division and the cell recovery from DNA damage. Our previous studies using cultured cancer cells, mouse tumor models, and patient tissue samples indicated that this enzyme is a potentially valuable anti-cancer drug target. Other laboratories independently confirmed it as a top candidate whose inhibition conferred specific toxicity in cancer cells, but not normal cells. It is therefore urgent to investigate the clinical targeting of this enzyme, in combination with existing regimens. In this project we will, for the first time, evaluate small molecule inhibitors of this enzyme in tumor cells and preclinical tumor models. This project will potentially achieve important milestones toward translating our new findings to new and enhanced treatment options for cancer, particularly triple negative breast cancer.
Eppley Institute for Research in Cancer and Allied Diseases, UNMC
A Novel Treatment for Pancreatic Cancer and Analysis of Its Therapeutic Mechanism
Currently, almost all pancreatic cancer patients die from their disease, even though standard treatments that doctors give can sometimes extend the patients’ lives for a few months. We have found that a drug called M344 can slow the growth of pancreatic cancer cells and make mice that have pancreatic cancer live longer. This research project will test this new drug against pancreatic cancer cells and mice with pancreatic cancer, in combination with a standard treatment for this disease, to see if the combination works better against pancreatic cancer than the standard treatment alone or M344 alone. Based on findings in our labs, we have some preliminary evidence about how M344 may be working against pancreatic cancer. In this project, we will do more studies to determine how M344 works against pancreatic cancer, because understanding the background of how medicines work enables medical researchers to develop better treatments rapidly and efficiently.
Department of Surgery,
Division of Cardiothoracic Surgery, UNMC
Optimization of In-situ Heart Reanimation During Donation After Circulatory Death
Despite continued expansion in the use of donor hearts following brain death, there remains an unacceptable discrepancy between the supply of suitable donor hearts and the demand from increasing recipient numbers of potential recipients on transplant wait lists. Donation after circulatory-determined death (DCD) is emerging as an alternative pathway to traditional donation after brain death (DBD). DCD heart transplantation has been made possible by technological developments in the fields of reanimation and preservation. In DBD donors, artificial ventilatory and hemodynamic (blood flow) support is used to keep organs in a fully functional state before transplantation. In DCD donors, the absence of respiratory and circulatory function deprives the organs of oxygen for a variable period of time before organ recovery. The current reanimation technique used after the heart stops working is to take the heart out of the donor body (ex-situ) and proceed to reanimate and preserve it by connecting it to a commercially available machine. A recently developed alternative is to restore circulation inside the donor body (in-situ) by connecting the circulation of the donor to the heart and lung machine and by using fully oxygenated blood to rapidly restore flow. Our long-term objective is to develop an optimal technique of inside-the-body reanimation and preservation of organs in donation after circulatory determined death. Our specific aims are to demonstrate improved heart function and decreased myocardial structural damage in organs initially perfused with cardioprotective solution in comparison to organs reanimated with fully oxygenated blood.
Department of Internal Medicine,
Division of Diabetes, Endocrinology, and Metabolism, UNMC
Identification of a Novel Metabolic Alteration in Obesity
Our long term goal is to determine how obesity alters the features of metabolic syndrome in particular, systemic insulin resistance, a pre-diabetes condition, which increases the risk for developing type 2 diabetes and cardiovascular disease in humans. It is becoming clear that adipose tissue or fat tissue not only serves as a storage organ for excess fat but also has a critical role in the metabolism of amino acids. It is an important site for the metabolism of certain types of amino acids called branched chain amino acids (BCAA) whose levels are increased in obesity and insulin resistance states. However, it is still unclear whether the metabolism of other essential amino acids are also altered in fat tissue in obesity. Moreover, the mechanisms by which amino acids alter obesity-linked inflammation and metabolic disorders remains unknown. In this pilot translational project, we collaborate with Drs. Cyrus Desouza and Corrigan McBride, to determine whether the metabolism of specific amino acids is altered in fat tissue in obesity. In addition, we will determine the potential mechanisms by which amino acid uptake and metabolism is regulated in fat tissue. The proposed study is relevant to identifying a previously unrecognized metabolic alteration in obesity which, in turn, will be helpful to develop novel drugs to treat obesity and/or type 2 diabetes in human population.
Department of Cellular and Integrative Physiology, UNMC
Mechanisms Driving the Anti-Hypertensive Actions of the Clinically-Tested Superoxide Dismutase Mimic, MnTnBuOE-2 -PyP5+
One in three American adults has hypertension. Although numerous anti-hypertensive therapies are currently available, about 30% of hypertensive Americans taking three or more of these drugs remain hypertensive. As a result, this group of individuals are at a greater risk of suffering from a major cardiovascular event, such as stroke or heart attack. Therefore, there is a critical need to develop new and improved medications for hypertension. Previous studies have clearly demonstrated that elevated levels of a reactive molecule known as superoxide in various organs, including the brain, contribute to the development and progression of hypertension. Further, our group and others have shown that reducing levels of superoxide by increasing an antioxidant, known as superoxide dismutase (SOD), significantly decreases hypertensive blood pressures. Many hypertensive Nebraskans and Americans (~30%) who are taking multiple drugs to treat their high blood pressure remain hypertensive. Therefore, there is a critical need to develop new medications for this disease. Our long-term goal is to translate novel SOD mimics to the clinic for the improved treatment of hypertension.