University Of Missouri Kansas City

NIH Research Projects · FY 2025 · 2024-07

Osteoporosis, a disease of reduced bone density that leads to bone fragility, is a major clinical problem and is primarily a disease of remodeling imbalance in which bone resorption outstrips formation. Although much progress has been made in defining the key genes and molecular pathways regulating osteoblast (OBL) and osteoclast (OCL) function and identifying targets for anti-resorptive and bone anabolic therapeutics, few studies have examined bone extracellular matrix (ECM) formation by OBL and subsequent resorption by OCL dynamically in live cells or living animals. Although the ECM was viewed as a static 3D scaffold, recent molecular imaging studies in OBL and other living systems have revealed the highly dynamic nature of ECM assembly and our work has shown that collagen fibril networks continually undergo movement, deformation and reorganization mediated by cell and tissue-generated mechanical forces. Studies with cells from mice with GFP-tagged type I collagen and a late OBL/osteocyte-targeted tdTomato reporter have enabled real-time imaging of collagen dynamics and OBL/osteocyte fate. This has revealed novel osteocyte differentiation/embedding mechanisms, including collagen trapping, cell movement into an already formed “collagen lacuna” or cells switching on osteocyte gene expression within an already formed lacuna. Recent intravital imaging has revealed the complexity of OCL cell dynamics and their responses to stimulators and inhibitors of bone resorption. This work suggests that RANKL induces OCL fission and recycling and that the RANKL inhibitor, OPG-Fc, causes accumulation of fissioned cells that may be re-activated upon withdrawal of RANKL inhibition. Based on these findings, the proposed studies center around two hypotheses. The first is that osteogenic cellular and differentiation dynamics are integrated with and dependent on collagen assembly, reorganization and mineralization dynamics and the second is that osteoclasts are highly dynamic cells that transition between different active states and their resorptive dynamics/activation states are differentially altered by agents that promote or inhibit bone resorption. Aim 1 will use mice expressing GFP-collagen and osteogenic lineage reporters for in vitro and intravital imaging to determine how osteogenic cellular dynamics, differentiation and cell fate are integrated with collagen assembly/mineralization dynamics and how these dynamics are altered by osteogenic factors. Aim 2 uses similar approaches to define the dynamics of OCL bone resorption, the dynamic interactions of OCL with osteocytes, their fate after bone resorption and how these are altered by agents that stimulate and inhibit bone resorption. 3D multiplexed imaging will be done on imaged bones to spatially map scRNAseq gene profiles at single cell resolution and correlate gene expression with cell dynamic histories to identify pathways driving osteogenic/osteocyte differentiation and OCL recruitment and activation. Successful completion of the aims may shift paradigms about the dynamic mechanisms of bone ECM assembly and resorption and the interplay between bone cell and ECM dynamics and will have important implications for our understanding of normal bone physiology and bone diseases, such as osteoporosis.

NIH Research Projects · FY 2024 · 2024-06

Project Summary This is a highly interdisciplinary research proposal to study the effects of aging on the responsiveness of osteocytes to mechanical loading in both sexes of mice. The proposal will engage undergraduate and graduate students alongside established investigators who will mentor these students in various aspects of bone mechanobiology, computer-based modeling to build in silico models of how osteocytes respond to load and 3D printing of osteocyte-lacuna-dendrite-canalicular models. The osteocytes with their interconnected dendritic network are thought to be the primary mechanosensory cells in bone. Aging produces changes in morphological aspects of the lacunar canalicular system. The long-term goal of this proposal is to determine how mechanical strain and fluid flow shear stress induce the biological activation (mechanotransduction) of bone forming pathways, such as the Wnt/β-catenin pathway, in osteocytes. Activation of this signaling pathway will be used to correlate with the mechanics that induce the cellular response. This will be done using sophisticated finite element (FE) and fluid-structure interaction (FSI) modeling, using confocal imaging, at the level of the osteocyte and its dendritic membranes using real data generated from loaded and unloaded bones as input into the models. The specific aims are to a) Develop multiplexed imaging models to predict osteocyte activation in response to altered mechanical loads encountered with aging, b) Develop macro and micro level 3D finite element and fluid- structure interaction models of osteocyte lacunae and determine the strains and shear stresses on osteocytes/dendrites as a function of age, at three different load levels and c) Correlate mechanical strain determined by in silico modeling to Wnt/β-catenin signaling for different load levels. Male and female TOPGAL (β-catenin reporter) mice at 6 and 18 months of age will be used. Activation of β-catenin signaling in osteocytes in the ulna in response to loading will be determined using novel multiplexed confocal imaging approaches to build multi-length-scale finite element models to study the loading response. From the 3D finite element and fluid-structure interaction models, strain fields in the lacuna and wall shear stress will be determined. Mechanical strain responses from in silico modeling will be correlated with the activation of osteocyte β-catenin signaling determined using confocal imaging in each of the osteocyte/dendrite systems (β-galactosidase activity) to determine a strain threshold for pathway activation. Fluid flow shear stress responses on the cell/dendrites will be studied using FSI models and magnitudes at the activation levels. Novel 3D printed models of the lacuna- canaliculi system will be used to study the overall flow of fluids through the system. The interdisciplinary research team, from the fields of bone biology and engineering, will train engineering and health science students in a collaborative team giving valuable experience to methods of working in diverse fields to research a scientific problem.

NIH Research Projects · FY 2026 · 2024-06

Project Summary Miscommunication in the Operating room (OR) is a leading cause of preventable error. Today’s OR is a loud, complex sound environment, threatening unobstructed communication between team members. Reducing hospital noise levels has been shown to have a direct impact on improving patient safety, yet today’s OR contains multiple, competing sound sources: surgical machinery coupled with intensified layers of simultaneous relevant and irrelevant conversations. These sources cause a specific type of miscommunication: Speech Communication Interference (SCI), impeding the team’s ability to communicate with each other, distracting from monitoring patient safety, and interfering with maintaining a safe care environment. There is a critical need to examine the larger context of the OR sound environment that leads to miscommunication. We propose groundbreaking research in surgical error prevention by applying Human Factors principles to OR miscommunication, including carefully selected evidence-based interventions from other industries. Our overall mission is to use a Human Factors approach to study the impact of the sound environment on communication in the OR and the execution of tasks necessary for monitoring patient safety. We will use the findings to develop and evaluate interventions to enhance overall communication in the OR. Using video and audio recordings, we will create detailed timelines surrounding Communication Interference events and interview the participants in that failed communication. Applying Human Factors frameworks will provide a rich understanding of the impact of overlapping conversations and environmental noises on patient safety. We will guide a team of content experts, including surgeons, anesthetists, nursing staff, and hospital leaders in the development and testing of interventions to improve OR communication. Outcomes will be measured, both pre-intervention and post-intervention, at three levels: the individual, process and system and will include important clinical outcomes such as hemorrhage and desaturation. We will use acoustical methods to predict noise interference and listener testing, for validation. Finally, we will test the interventions at a second hospital to ensure generalizability. The study will occur at University Health Medical Center and Childrens Mercy Hospital, providing care to underserved patients, many without commercial insurance. Our lab has years of experience videorecording in the OR, creating timelines, and conducting interviews, finding that they have an unparalleled ability to uncover near misses. This project will result in a set of innovative interventions, grounded in a systems approach, to prevent, mitigate, and recover from miscommunication, and will lead to a multi-center trial to test the effect of our OR communication interventions on patient safety in diverse OR settings.

NIH Research Projects · FY 2026 · 2023-07

Project Summary/Abstract Voltage-gated sodium (Nav) channels are integral membrane proteins that selectively conduct Na+ ions across cell membranes. They are associated with cardiovascular, neurological, and psychiatric disorders and are the molecular targets of widely used antiarrhythmic, anticonvulsant drugs. The human Nav1.5 channel generates cardiac action potentials and is associated with life-threatening arrhythmias. The atomic structure of Navs was first obtained from a prokaryotic NavAb channel in 2011, and then more eukaryotic Nav structures were solved by cryo-EM in recent years, including the human cardiac Nav1.5 channel. Both the prokaryotic and eukaryotic Nav channels are very similar in structure, including their selectivity filters, ion permeation pores, voltage sensors, and pharmacological profiles. Most recently, the resting and activating conformations of NavAb channels were obtained by combining the function-dependent cross-linking and cryo-EM, which provided basic molecular frameworks to further investigate the mechanisms of voltage gating and drug modulation. My project aims to reveal dynamic behaviors of the selectivity filter pores and voltage sensors in NavAb and Nav1.5 channels and the effects of permeant/blocking ions, gating voltages, and drug molecules on them. We will implement the cutting-edge single molecule fluorescence resonance energy transfer (smFRET) approach to achieve these proposed studies. Specifically, we will use both the model NavAb and human Nav1.5 channels to (a) uncover the conformational flexibilities and dynamics of the Na selectivity filter and elucidate how it can selectively conduct Na+ over cations such as K+ and Ca2+; (b) define the roles of selectivity filters in slow inactivation, and understand how antiarrhythmic drugs like lidocaine and flecainide alter them to inhibit channel function; (c) reveal the real time conformational transitions and dynamics of the voltage sensor and channel gate in NavAb and Nav1.5 channels that is directly driven by the electrical potential to elucidate the mechanism underlying voltage sensing and gating. We have obtained very exciting preliminary data on the NavAb channel, which strongly justified the significance and feasibility of the proposed studies. In the resubmission, we further made the key technical advances by establishing the unnatural amino acid incorporation method, which allows us to label the human Nav1.5 channel with fluorophores for smFRET studies. With the Nav1.5 channel, we will validate the key findings made on the NavAb channel and reveal the dynamic properties that are unique for eukaryotic Navs. My studies will provide fundamental mechanistic insights into the ion selectivity, voltage gating, and drug modulation of Nav channels, which will have broad implications on other channels and transporters by providing both conceptual advances and novel methodologies.

NIH Research Projects · FY 2025 · 2023-07

In the past 40 years, fungal diseases have emerged as a pressing health concern, as incidence rates have increased markedly, novel pathogens have emerged, resistance to antifungal drugs has risen and prevalence of immunosuppressive conditions has increased. Environmental conditions may exacerbate fungal disease risks by shifting the suitable habitat for pathogenic environmental fungi, lengthening the transmission season of spores, and dispersing spores via extreme weather events. An understanding of the effects of environmental conditions (wind, soil composition and moisture, floods, temperature extremes) and patient risk factors (rural residence, limited insurance coverage, low-income) on the distribution and severity of fungal diseases is critical to protecting the health of high-risk groups. To date, epidemiologic studies of fungal diseases in the U.S. have been limited in spatiotemporal scope and sample size, precluding robust characterization of risk factors and outcomes among patient subpopulations. While largely untapped as a resource for investigating fungal disease, electronic health record (EHR) and infectious disease surveillance systems generate massive health datasets that can be used to estimate risk factors for fungal infections, including candidiasis, cryptococcosis, aspergillosis, blastomycosis, histoplasmosis, coccidioidomycosis and dermatomycosis. Via partnership with Oracle/Cerner (Austin, TX), we will analyze deidentified EHR data for over 96 million patients, 1.4 billion visits, and 4.7 billion clinical events. A subset of the databases is available with geographic locations of patient 3-digit zip codes. We will also analyze surveillance data on all reported cases (>95,000) of coccidioidomycosis in California since 2000, geolocated to patient address. After addressing misclassification, selection, and missing data biases in the EHR, our team will estimate regional trends in incidence, hospitalization and mortality rates for fungal diseases in the U.S. We will apply modern time series approaches to understand the role of environmental conditions in fungal disease epidemiology, estimating the association between temperature, precipitation, soil moisture, and other factors on fungal disease incidence and emergence. We will investigate the impacts of extreme events such as heat waves, dust storms, tropical cyclones and flooding on incidence, and will determine whether exposure-response relationships are modified by patient risk factors. We will examine the role of individual- and community-level factors—such as preexisting comorbidities and housing quality—on fungal disease outcomes, and will forecast near-term trends in incidence. The project will yield robust understanding of the environmental epidemiology of major mycoses in the U.S., and the role of environmental conditions, patient risk factors and community-level factors in exacerbating disease risks.

NIH Research Projects · FY 2026 · 2023-04

Project Abstract To ensure survival , animals must satisfy a variety of needs that lead to what are often mutually exclusive motivated behaviors. An example of such a behavior is sleep, a process that has been described in a variety of species ranging from jellyfish to humans. Although the precise function of sleep remains unknown, there is ample evidence supporting the notion that sleep is required for maintaining optimal physiological and behavioral performance. Importantly, sleep is regulated by two processes, the circadian clock which gates the occurrence of sleep, and the sleep homeostat which controls the intensity and duration of sleep. Beyond the clock and the homeostat, a variety of sensory inputs and internal states can modulate sleep in significant ways. For example, animals can dramatically modify, reduce, or completely forego sleep if their internal needs and/or external circumstances demand it. Importantly, sleep competes with other essential motivated behaviors, such as feeding. This implies that the decision to engage in, remain in, or exit sleep behavior must be weighed against the drive to perform other key motivated behaviors. Thus, to maximize survival, organisms must constantly assess their environment and their internal needs and alter their physiology and behaviors accordingly. The mutually exclusive nature of sleep and feeding behaviors implies that each of these individual motivational drives must not only be able to modulate the neuronal circuits underlying their associated behavior but also those of the competing one. Although much is known about neural circuits regulating individual behaviors, interactions between them are less well characterized. Understanding how behavioral decisions are made, and how the neuronal circuits underlying different behaviors interact, is a key aspect of modern neurobiology that will help us understand how the nervous system can help organisms adapt to an ever-changing environment and prioritize behaviors in a way that maximizes survival. We have identified two novel sleep- promoting neurons in the Drosophila central nervous system. Interestingly, these neurons also modulate feeding. In addition, we discovered that the activity of these two neurons is regulated by diet composition. In this proposal, we will use the power of the Drosophila model to investigate how these two neurons modulate sleep and feeding. We will identify the circuits, genes and neuromodulators involved in these relationships. Since the molecular mechanisms that regulate feeding and sleep are evolutionary conserved between Drosophila and mammals, we anticipate that this proposal will uncover regulatory principles that are relevant to human physiology. .

NIH Research Projects · FY 2026 · 2023-04

Project Summary/Abstract The precise and largely stereotyped connectivity patterns of neurons underlie simple knee-jerk like reflexes and complex behavior, like playing the violin. While we have a good understanding of the conserved genetic and molecular mechanisms that drive the initial steps of nervous system formation, we possess a far more rudimentary knowledge of those that drive neural circuit formation and animal behavior. By focusing on the development and function of the Drosophila adult ventral nerve cord (VNC), which controls behaviors, such as walking, flying, and grooming, our research leverages the power of the fly model system to dissect the genetic and cellular basis of neural circuit formation and behavior. Like the vertebrate spinal cord, the Drosophila adult VNC is composed of segmentally repeated pools of lineally related neurons. In Drosophila, these pools of neurons are termed hemilineages and are the basic developmental and functional unit of the VNC. We have previously mapped the embryonic stem cell origin, axonal projection pattern, transcription factor expression, and neurotransmitter usage of all 34 hemilineages that comprise the adult VNC. In general, however, we lack a clear understanding of the behaviors each hemilineage regulates, the neural circuits within which each hemilineage resides, and most of all the genes that act within each hemilineage to regulate its connectivity and associated behaviors. The goals of this proposal are to elucidate the functions of two conserved transcription factors – the homeodomain-containing protein Hb9 and the Pou-domain containing protein Acj6 – in regulating neuronal connectivity and behavior in each of the six hemilineages in which they are expressed (aim 1), to map each Acj6- or Hb9-positive hemilineage to its associated neural circuit and behavior(s) (aim 2), and to construct a split-GAL4 library that will allow one to uniquely target gene and cell function in every hemilineage in the adult VNC (aim 3). Successful completion of these aims will initiate a systematic dissection of the transcriptional regulatory networks that act within the adult VNC to govern neuronal connectivity and behavior and help build a comprehensive map that links all VNC hemilineages to their associated neural circuits and behaviors. It will also create a genetic toolkit that will allow any lab to dissect gene and cell function in essentially any hemilineage of the adult VNC, facilitating the elucidation of the genetic and cellular basis of behavior. Given the strong parallels between the molecular pathways that govern CNS development in flies and vertebrates, our research holds great potential to uncover conserved genetic principles that underlie neural circuit formation and behavior from flies to humans.

NIH Research Projects · FY 2026 · 2023-04

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality in the world. Desmoplasia is the most prominent characteristic of PDAC and comprises up to 80% of the tumor mass. Desmoplasia plays important roles in tumorigenesis and aggressiveness by promoting the proliferation and metastasis of tumor cells, enhancing angiogenesis, impeding drug penetration, and contributing to immune evasion. However, clinical trials employing strategies to deplete PDAC stroma have failed. The stroma acts not only as a barrier to the penetration of drug and effector T cells, but also as a barrier to restrain the metastasis of PDAC tumors. Complete depletion of the stroma, therefore, leads to a more aggressive tumor and a poor survival rate. By contrast, normalization, instead of depletion, of the stroma in combination with chemotherapy or immunotherapy to kill tumor cells within the stromal microenvironment is a promising strategy for PDAC therapy. In the stromal microenvironment, activated pancreatic stellate cells (PSCs) transform from a quiescent state into a myofibroblast-like phenotype and express a large amount of extracellular matrix (ECM). Type I collagen proteins are the main component of the ECM and are responsible for the major desmoplastic reaction. High levels of type I collagen are associated with a low survival rate for patients with PDAC. Type I collagen promotes the proliferation and migration of PDAC cells and inhibits apoptotic cells by binding to integrin. We discovered that silencing the poly(rC)-binding protein 2 (αCP2) with siRNA reverses the accumulation of type I collagen in activated PSCs. Our central hypothesis is that silencing αCP2 modulates the PDAC stroma, thus improving the therapeutic index of chemotherapy and immunotherapy. The long-term goal of the project is to develop a combination therapy strategy to treat PDAC.

NIH Research Projects · FY 2025 · 2022-07

Abstract Debilitating hear loss affects over 6% of the world’s population and can result in a profound decrease in the quality of life for those afflicted. Hearing is mediated by mechanosensory hair cells located in the cochlea of the inner ear. Another population of hair cells in the inner ear makes up the vestibular system to relay the sensation of balance and gravity. Hair cell damage results in sensory defects. The causes of hair cell damage include age, noise exposure, ototoxic drugs, disease, and injury. In adult mammals, once hair cells are lost, they do not regenerate, resulting in permanent hearing loss and balance disorders. In addition to mediating the sensations of hearing and balance, mechanosensory hair cells are also required for close touch sensation in the lateral line systems of aquatic vertebrates. Lateral line hair cells are morphologically and genetically very similar to inner ear hair cells. In contrast to the inner ear hair cell of mammals, the hair cells of the lateral line system are robustly regenerative. The zebrafish (Danio rerio), has emerged as a valuable model to study the mechanisms of mechanosensory hair cell regeneration. Research using pharmacological manipulation of the canonical Wnt pathway suggests that it is critical for regulating the cellular proliferation and differentiation required for hair cell regeneration. To genetically confirm a role for Wnt signaling during regeneration, we will use three zebrafish lines carrying mutations at different points in the Wnt pathway. In Aim 1, we will characterize hair cell regeneration in the krm1nl10 mutant, which results in overactivation of Wnt signaling. In Aim 2, we will characterize regeneration in the lef1nl2 mutant line, which results in an inhibition of Wnt activity. In Aim 3, we will examine regeneration in a third line, foxg1aa266, which contains a mutation in the Wnt transcriptional target gene foxg1a. Together, we will use these lines to determine how cellular proliferation, differentiation, and survival are regulated by the Wnt pathway during regeneration of mechanosensory hair cells. The long-term goal of this work is to provide a mechanism for regenerate hair cells in the human inner ear.

NIH Research Projects · FY 2025 · 2022-04

PROJECT ABSTRACT Wide-reaching efforts are needed to increase population levels of physical activity and healthy eating in low- income groups for obesity- and type 2 diabetes prevention/control. Low-income groups experience higher rates of obesity and diabetes than the general population and the COVID-19 pandemic has made these groups even more vulnerable to developing these preventable chronic diseases. Active transportation is an underused source of physical activity but is particularly relevant to low-income groups. A major and consistent correlate of active transportation is use of public transit, and transit users engage in 5-15 more minutes/day of overall PA that non-users. Public transit may also support access to healthy eating and health services. Citywide policies to increase use of public transit have promise for improving health markers but have been substantially underexplored. As an effort to improve economic conditions among low-income groups, Kansas City, MO (KCMO; 500K residents; 43,000 daily bus trips) has become the only major city in the U.S. to permanently adopt an ongoing zero-fare bus transit (ZBT) policy. The policy has eliminated all bus fares across the city. This provides an extraordinary opportunity to examine impacts of such policies on bus ridership and subsequently on bus users' physical activity, healthy eating, and weight status. In this proposed study, we will collect bus ridership data before and up to 3 years after ZBT in KCMO and multiple comparison cities. To investigate health information, study participants will be recruited from a large primary care health system serving low- income communities. Participants will complete measures of bus use, and height and weight information will be obtained from the health system's electronic health record before and up to 3 years after ZBT. A subsample of participants will complete a 7-day objective physical activity assessment and questionnaires on their healthy eating, perceptions of the ZBT policy, and barriers/facilitators to riding the bus. Community residents will collect neighborhood environment information around bus stops to test as barriers to bus ridership and support advocacy efforts. A state-of-the-art synthetic control approach will be used to compare ridership trends across cities and weight status trajectories between post-ZBT bus users and non-bus users. The synthetic controls will be a weighted combination of multiple control participants to provide a better comparison than any single control alone. This study has significant implications for advancing knowledge and evidence on the potential health impacts of ZBT policies. Findings will produce information that will be usable by other natural experiment researchers and healthcare entities, as well as by local, state, and federal governments in making determinations on use of public policy approaches such as ZBT as a lever for obesity- and diabetes-related risk reduction in low-income communities.

NIH Research Projects · FY 2024 · 2020-04

PROJECT SUMMARY African Americans (AAs) are disproportionately burdened by diabetes mellitus (DM) with rates twice as high as Whites (13% vs 7.5%), and increased rates of DM-related complications and comorbidities (e.g. amputations, cardiovascular disease). A key pre-DM risk factor is overweight/obesity. Nearly 70% of AAs are overweight or obese, with higher rates among AAs with low-income. A critical component of national efforts to reduce growing obesity rates and prevent DM is the Diabetes Prevention Program (DPP), a lifestyle intervention proven to reduce or delay DM onset with diet change, exercise, and modest weight loss (5-7%) in a rigorously evaluated national trial. A group-based version of the DPP has been widely disseminated and numerous community-based trials support its efficacy. In spite of these successes, there are significant health disparities in DPP attendance and outcomes and considerable room exists for improving success rates among AAs, a population that tends to experience half the amount of DPP weight loss compared to Whites. We aim to build on our promising pilot studies by tailoring the DPP via a social determinants (SD) of health lens to achieve optimal DPP attendance and clinically meaningful weight loss with pre-DM AAs. This includes tailoring on cultural and socioeconomic SD mechanisms that are associated with improving health outcomes and align with predisposing needs among AAs who are primarily of low-income and live in low-resource AA communities. We propose a randomized controlled trial of 360 pre-DM AA patients from a safety net hospital (SNH) to test a standard DPP (S-DPP) against a culturally tailored DPP (TC-DPP; e.g., tailoring of language, foods, values, religiosity, norms, values) alone and a culturally tailored DPP enhanced to address access and support related economic barriers (TCE-DPP; hybrid group/online/text DPP; community health worker support to improve access to DPP classes, healthy food, exercise, and other community and health resources; and financial incentives) over 12 months. We will: 1) examine effects of TC-DPP and TCE-DDP on percent weight loss and attendance (primary outcomes) and on secondary outcomes (physical activity, completion of physician follow- up visit, hbA1c, and blood pressure) at 6 and 12 months with SNH AAs, 2) evaluate potential mediators/ moderators related to weight loss and attendance among AA SNH patients at 6 and 12 months to determine modifiable facilitators and barriers, and 3) conduct a process evaluation to examine TCE-DPP acceptability, feasibility, and fidelity, and relationships between delivery dose, exposure, costs, and outcomes to identify and improve essential intervention components. Our multidimensional DPP interventions are guided by our past pilots, and based on components that, all together, were used to help drive clinically important outcomes in the original DPP trial – and are certainly needed to achieve similar outcomes with AA primarily of low-income. To our knowledge this is the first study to test multidimensional tailoring via an SD lens to truly impact DPP attendance and outcomes, and has potential to be a feasible, scalable model to reduce DM disparities among at-risk AA.

NIH Research Projects · FY 2025 · 2012-07

Project Summary/Abstract As the leading cause of death and disability in the United States, cardiovascular disease has benefitted from immense research investments to improve the care of afflicted patients. However, the application of this knowledge in routine clinical practice has been variable and the evaluation of more patient-centered outcomes, including patients’ symptoms, function and quality of life, are desperately needed. Not only do these knowledge gaps limit the potential for US healthcare to improve, but evolving changes in reimbursement from a volume- to value-based payment models have created an unparalleled demand for cardiovascular outcomes researchers. This renewal application seeks to continue a highly successful program for training post-doctoral scholars to independently perform clinically-oriented outcomes research. It extends and improves the University of Missouri- Kansas City (UMKC)’s outcomes research training program, which is unique in the Midwest and serves as a central unifying research program for our region. The 2-year training program has 3 synergistic components: 1) a basic foundation of in clinical research (including a Masters degree in bioinformatics with a clinical research emphasis), 2) specialized skills for outcomes research coupled with academic ‘survival skills’ (our outcomes- based core curriculum), and 3) hands-on research. Hallmarks of the research experiences include multi- disciplinary group mentorship, individualized mentorship to meet each trainee’s needs; access to numerous existing data, as well as clinical populations for primary data collection and implementation; training in entrepreneurship; and highly experienced statistical support. Enhancements planned for the existing program include 1) a more robust collaboration with the University of Missouri system, which is investing in the NextGen Precision Medicine institute and for which our program serves as the central pillar for precision healthcare delivery; 2) increased engagement in clinical trial design and execution; and 3) access to a new community collaboration of 19 regional hospitals innovating healthcare delivery to improve its value (www.kcqvic.org) for deeper exposure to implementation research. Administering the program will be an experienced program director, supported by well-qualified associate and assistant directors and mentors with expertise in economics and decision analysis; large database analysis; bioinformatics; qualitative and implementation research; study design, methodology and statistics; patient and clinician behavior change; community-based participatory research; entrepreneurship; shared medical decision-making and patient-centered research; multi-disciplinary cardiovascular research; disparities research; and risk models and creation of clinical tools, as well as an advisory committee of national leaders. Collectively, our committed team will provide a formal training, mentorship and evaluation program to continue and enhance our prior success in supporting the ability of trainees to make significant contributions to the scientific literature and to embark on successful academic research careers.