The goal of the Thematic Research Project Program is to provide support to junior faculty pursuing high-quality biomedical research projects that will be competitive for NIH R-type or other external health-related funding sources. Although all areas of biomedical research may be considered appropriate for INBRE support, INBRE encourages the submission of proposals that focus on at least one of the INBRE–4 thematic areas: 1) Cell and Molecular Biology; and 2) Methods for Chronic Disease Research and Therapies. Proposals must be single investigator and the maximum award varies from $75-100,000. Outstanding proposals from junior investigators (tenure-track Assistant Professors), particularly those who have not received substantial previous INBRE support, will receive highest priority. Junior investigator applicants must identify a mentor. In addition, the integration of faculty and students from Wyoming community colleges is strongly encouraged.
YEAR 5
Renewal Year - No new thematic award competition
Year 4
Christina McDonnell
Grace Shearrer
Year 3
Nicole Bedford
Ana Clara Bobadilla
Elizabeth Case
Katelyn Kotlarek
Year 2
Eunsook Park, Assistant Professor, Molecular Biology. Autophagy: a new target biological process to develop effective antifungal drugs for human fungal diseases. Cryptococcus neoformans causes morbidity and mortality in immunocompromised people, yet there still is no effective therapy to prevent this infection. About 4 million death associated with AIDS-related death has been attributed to the fungal infection in the past decades. Many fungal pathogens of clinical importance, including C. neoformans, are dimorphic, and the morphological status often associates with their virulence. C. neoformans have a striking life cycle depending on the environmental niche. The sexual life is observed on C. neoformans-plant interaction, while it has asexual morphology inside vertebrate hosts. Although basidiospores at the end of the sexual life are infectious propagules and capable of colonization in human lung, current knowledge for the pathogenesis of this fungus has been limited. Thus, it is necessary not only to understand the molecular mechanism of the life cycle of C. neoformans adapted to dual compatible hosts of both animal and plant but also to identify effective fungicides against the infectious fungal pathogen for the prevention of diseases and improvement of healthcare. Preliminary results from other fungal pathogens indicated the importance of autophagy in several key developmental processes of fungi in their sexual life cycle. In addition, autophagy mutant of C. neoformans showed compromised pathogenicity, suggesting the tight connection of autophagy and pathogenicity and dimorphic life cycles of C. neoformans. Therefore, in this study, we will identify fungal autophagy-specific inhibitor by an innovative high throughput chemical screening using versatile Bioluminescence Resonance Energy Transfer (BRET)-based sensors. In addition, we will dissect the role of autophagy at the host-fungus interface in Cryptococcosis disease development. The proposed study will not only expand our limited knowledge on the molecular mechanisms of autophagy at the interface of fungal pathogen and host interaction but also envision developing novel therapies to combat C. neoformans for human health.
Emily Schmitt, Assistant Professo, Kinesiology and Health. The mammalian circadian clock coordinates many biological processes from behaviors to cellular metabolism and mitosis and is coordinated in a 24-hr rhythmic pattern. A central molecular clock known as the suprachiasmatic nucleus (SCN), located in the hypothalamus, acts as the pacemaker to multiple circadian oscillators including those in peripheral tissues where key circadian rhythm genes are expressed. Frequent jet lag or shifts of daily rhythms as a result of rotating shift work disrupt the circadian clock and can lead to many deleterious health outcomes including breast cancer and reproductive disorders in women, as well as cardiovascular disease, stroke, and metabolic syndrome in both men and women. Therefore, identifying ways to mitigate the harmful consequences that arise from circadian disruption that negatively impact human health is imperative. Little is known about the mechanisms that control physiological consequences from shift work. The proposed project is designed to understand how exercise can mitigate circadian disruption. Determining the harmful impacts of circadian disruption and using physical activity to mitigate the harmful effects from circadian misalignment is a novel solution to combat chronic diseases that arise from shift work. The overall approach is to use exercise as a treatment to restore molecular clock disruption, either through a chrono-timed treadmill exercise protocol experiment or lifelong exercise on a running wheel. Our goal is to determine how exercise can re-entrain the central and peripheral clocks in both male and female mice. Specifically, we aim to test how chrono-timed exercise can re-entrain the misaligned molecular clock (Aim 1) and how lifelong exercise can provide protection from circadian disruption (Aim 2).
Year 1
Thomas Boothby, Assistant Professor, Molecular Biology. Developing strategies for the long-term preservation of Drosophila stocks. Laboratory animal models, such as the fruit fly Drosophila melanogaster, are essential to understanding human health and disease and facilitating the development of diagnostic approaches and therapeutic interventions. A large number of valuable genetic fly strains are being generated at an unprecedented pace due to the rapid advances in genome editing tools. However, this increase in genetic stocks creates challenges in maintenance, preservation and sustainability of these resources. Currently, there are over 60,000 Drosophila stocks at the NIH-supported Bloomington Drosophila Stock Center all of which must be maintained as labor intensive live cultures. Therefore, there is an urgent need to achieve simple, reliable and cost-effective methods for long-term preservation and revival of Drosophila. To address this problem, we will develop technology for the long-term storage of Drosophila embryos in a dry state. While water is essential for the viability of most living systems, there are some organisms that can survive being desiccated. One such system is the tardigrade, a tiny animal, which possesses three families of intrinsically disordered proteins (IDPs) that are necessary for them to survive drying, are sufficient to increase the desiccation tolerance in heterologous systems (e.g., yeast and bacteria) by up to 100X, and preserve sensitive purified biomaterials (e.g., enzymes) up to an order of magnitude more efficiently than current FDA approved protectants. We will achieve our goal of developing technology for the dry preservation of Drosophila embryos through the execution of three specific aims. Aim 1: we will carry out a series of quantitative assays coupled with advanced fluorescence microscopy to understand what perturbations arise in cultured, desiccation-sensitive, Drosophila S2 cells as well as one cell-stage embryos. Aim 2: we will develop strategies using our existing knowledge of desiccation tolerance to prevent these perturbations in S2 cells, for example by the introduction of tardigrade IDPs and other protectants. Aim 3: we will apply the lessons learn in Aim 2 to develop technology allowing us to preserve one-cell stage Drosophila embryos in a dry state. Completion of these three aims is in line Wyoming INBRE-4’s thematic goals. Aim 1 will define the cellular and molecular perturbations induced by a pertinent stress (desiccation), while Aims 2 and 3 will develop technology to enhance the value and utility of Drosophila, a key model for the study of chronic human disease. INBRE support of this project will be essential for developing a future grant that is competitive in NIH’s PAR-19-176 funding announcement or similar solicitations.
Danielle Bruns, Assistant Professor, Kinesiology and Health. Identification of juvenile factors to treat age-related declines in cardiac adrenergic reserve. Heart failure (HF) is an enormous public health problem which impacts patients across the entire human life-course. Traditionally, HF has been treated with a one-size-fits-all approach, a strategy which has largely been unsuccessful, as evidenced by stagnant 5-year mortality over the last few decades. We believe this is in part due to significant differences biological variables such as age, which influences disease pathogenesis between the young and old patients. We recently tested this hypothesis in pediatric, adult, and geriatric mice treated with the same stimulus- adrenergic activation by isoproterenol (ISO). While pediatric mice robustly responded to ISO to increase cardiac contractility, the aged mice did not. Our preliminary data also demonstrate significantly different pathway activation by age, with pediatric hearts robustly upregulating genes implicated in cardiac and sarcomere contractility, a molecular signature completely absent in the aged heart. Thus, our overall hypothesis is that factors present in the pediatric heart must be responsible for its responsiveness to ISO, and that these factors change with increased age. We propose that identifying these putative protective factor(s) will improve therapeutic options for older patients with HF who are well-characterized by diminished responsiveness to ISO. The purpose of this INBRE Thematic Proposal is to identify these factors by mechanistic dissection of the adrenergic signaling cascade in pediatric and geriatric mice. We will specifically test whether differences in adrenergic receptor activity or downstream sarcomere protein and mechanics are responsible for the different responses to ISO between pediatric and geriatric mice. This Thematic Research Project proposal comes from a junior faculty currently supported by a Career Development Award (K) from NIH. This K award provides Dr. Bruns with the scientific and professional training as well as mentorship team necessary to build a successful independent career in the field of cardiac aging. While this proposal does not scientifically or budgetarily overlap with the K, it allows Dr. Bruns to take advantage of the training and mentorship she’s received during the K, using similar techniques to answer similarly significant biomedical research questions. Further, this proposal integrates WY community college collaboration in Dr. Bud Chew’s group to comprehensively assess the mechanisms by which the pediatric and geriatric hearts respond differently to the same stress. Together, this Thematic Research Project will support the generation of preliminary data to continue Dr. Bruns’ lab efforts to treat HF in the aging population and accelerate her trajectory and promise for future R-level funding in this significant area of biomedical research.
Todd Schoborg, Assistant Professor, Molecular Biology. Role of glial cells and the inflammatory response in brain growth control. Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by reduced brain size and life span resulting from mutations in MCPH genes. While the clinical aspects of the disorder are well characterized, the underlying molecular mechanisms remain poorly understood. This has limited our ability to fully understand how genetic & cellular defects contribute to altered tissue function in MCPH patients. This proposal seeks to uncover the mechanisms by which MCPH genes promote proper brain size, leading to a better understanding of brain development, growth and evolution. Specifically, it focuses on the role of abnormal spindle (asp) and WD repeat containing protein (wdr62), the two most commonly mutated genes in human MCPH patients, exclusively in glial cells. The role of glial cells in brain growth control has been largely ignored in the context of MCPH, despite their involvement in other neurodegenerative disorders. Recent work has shown that wdr62 activity in glial cells is important for proper brain size in Drosophila, and my preliminary data on asp mutant brains suggests activation of an inflammatory response, likely mediated by glia. This proposal is designed to dissect the relationship between asp & wdr62, glial cells, the immune response, and other cellular pathways in the etiology of MCPH. To do so, we will utilize Drosophila genetic tools, reporter assays and high resolution imaging to test a series of hypotheses for how glial cells influence brain growth. Completion of this project will not only identify and characterize a novel cellular pathway for MCPH, but also lay the foundation for a future R01 grant aimed at dissecting the molecular mechanism of glial cell function in brain growth control.
Pejman Tamasebi, Assistant Professor, Petroleum and Civil Engineereing. Cell-Based Blood Flow Simulation using a Coupled Blood-Cell Modeling. Several challenges avoid modeling the behavior of living tissue, such as flowing blood, from a biomechanical viewpoint. This problem has been investigated as a fluid that contains solid particles; e.g. cell transport in blood flow, and platelet deposition on blood vessel walls. Due to complex interactions between the particles and blood, their dynamic behavior is a very complicated problem. The existing cells and elements in blood adapt their functions and configurations to their environment and they continuously change the morphology and behavior. This characteristic must be taken into account in the modeling process. More typical examples are blood coking, drug carrier design, cell separation, blood clotting, flow-induced blood clotting and thrombus formation in cardiovascular pathologies, and in cardiovascular devices. Furthermore, the presence of highly deformable particles makes such problems very challenging. The available methods treat all the constituents in the blood flow field by a unified method and adopting a particle-based method such that the plasma flow, as well as the motion of the cellular components, is modeled via particle-based representations. For instance, the solid components are modeled as connected particles whose connection is fixed and can be deformed unrealistically. Although various numerical methods have been proposed, there is a growing interest in the particle-based methods and a crucial need for a method that can take the real morphology of cells and particles into account. In this research, we plan to study such an important phenomenon by considering the particles as deformable cells that are similar in morphology in the vessel, thus requiring explicit consideration of the particle mechanics. We aim to conduct such simulations for the first time and provide very realistic results of the interactions between deformable particles and blood. It should be noted that other than the morphology, we also plan to consider the softness degree (i.e. plasticity) for the utilized particles such that they can experience a plastic and elastic deformation. The results of this research will provide an accurate calculation of the lubrication forces between particles as well as long-range hydrodynamic interactions among many interacting cells. Furthermore, this method will be a type of molecular dynamics modeling and can be used to phenomena in the nanoscales where biochemistry plays a major role.
Evan Johnson, Assistant Professor, Exercise Physiology, UW. Genetic and Hematological Risk for Acute Kidney Injury during High Intensity Exercise.
Jill Keith, Assistant Professo, Family and Consumer Sciences, UW. Reclaiming indigenous food and health: a pilot RCT on health impacts of sovereign nation diets.
Breanna Krueger, Assistant Professor, Communication Disorders. Age-related correlates of treatment efficacy and efficiency for late-acquired sounds.
Katie (Dongmei) Li-Oakey. Assistant Professor, Chemical Engineering. Tunable Biodegradable Multimodal Hydrogel Nanoparticles for Targeted Therapeutics.
Alison Looby, Assistant Professor, Psychology. Examining Expectancy Challenges to Prevent Nonmedical Prescription Stimulant Use.
Maysam Mousaviraad, Assistant Professor, Mechanical Engineering. Computational FSI Modeling for Heart Failure Treatment with Titin Manipulation.
Rebecca Carron, Assistant Professor, School of Nursing. Polycystic Ovarian Cancer in American Indian Women: An Exploratory Study.
Brian Cherrington, Assistant Professor, Zoology and Physiology. The Effect of Obesity Induced Hyperinsulinemia on Lactation.
Wei Guo, Assistant Professor, Animal Sciences. Role of RBM20 in the regulation of cardia gene splicing in heart failure.
Guanglong He, Associate Professor, School of Pharmacy. CARD9 Signaling and Childhood Obesity-Associated Cardiac Dysfunction.
Anya Lyuksyutova, Assistant Researcher, Molecular Biology. Optogenetic control of GCS via microRNAs as treatment for liver Steatosis.
Amy Navratil, Assistant Professor, Zoology and Physiology. Molecular Mechanisms of Lutenizing Hormone Disregulation in PCOS.
John Oakey, Assistant Professor, Chemical Engineering. Circulating tumor cell capture and release from degradable hydrogel surfaces.
Christine Porter, Assistant Professor, Kinesiology and Health. Growing Resilience Phase II: Albany County Redesigns and Wind River Expansions.
Baskaran Thyagarajan, Assistant Professor, Pharmacy. TRPV1 Activation Prevents from High Fat Diet-Induced Non-Alcoholic Ftatty Liver Disease (NAFLD) in Obesity via SIRT-1.