Announcements Funding CTRFP Awardees ICTS News

ICTS Announces 2023-2024 CTRFP Awardees

(1st row, left to right) Grant Challen, PhD; Eric Duncavage, MD; Antonina Frolova, MD, PhD; Joseph Gaut, MD, PhD; Kirsten Gilbert, PhD; Jaya Gnana-Prakasam, PhD; Lakshmi Gokanapudy Hahn, MD (2nd row, left to right) Kelly Harris, PhD; Caroline Hoyniak, PhD; Patricia Jimenez, MD; Carol Kao, MD; Christopher King, MD, PhD; Brian Laidlaw, PhD; Osvaldo Laurido-Soto, MD (3rd row, left to right) Whitney Linsenmeyer, PhD; Changqing Ma, MD, PhD; Aaloke Mody, MD; Oluwatoyosi Owoeye, MS, PhD, BPT; Russell Pachynski, MD; Arvind Palanisamy, MD, FRCA; Mary Politi, PhD (4th row, left to right) Lixing Reneker, PhD; Ahmed Said, MD, PhD; Pawan Kumar Singh, PhD; Stephen Stone, MD; Regina Triplett, MS, MD; Amanda Verma, MD; Ofer Zimmerman, MD

Washington University Institute of Clinical and Translational Sciences (ICTS) and The Foundation for Barnes-Jewish Hospital awards 28 investigators as part of the 16th annual Clinical and Translational Research Funding Program (CTRFP). The CTRFP is the largest internal grant funding program of the ICTS. Applicants are required to submit proposals for projects that promote the translation of scientific discoveries into improvements in human health. For 2023, awards were considered across three project categories: clinical/translational, community-engaged research, and biostatistics, epidemiology, and research design.

This year the CTRFP received over 100 letters of intent and awarded approximately $1.3M for investigator-initiated projects. These grants are supported with funding from the ICTS, The Foundation for Barnes-Jewish Hospital and ICTS partner institutions: Saint Louis University and the University of Missouri-Columbia.

Funding is made available to the 2023 awardee cohort effective March 1, 2023.

Detecting Occult Malignancy in Pleural Fluid using Comprehensive Methylation Profiling

PI: Grant Challen, PhD
Washington University School of Medicine: Department of Medicine, Division of Oncology

Lung cancer often presents with disease involving the lining of the lungs, termed malignant pleural effusion (MPE). Accurately diagnosing an MPE is essential for selecting the correct treatment. Cytology is the standard diagnostic tool, but is only positive 60% of the time when an MPE is present. We seek to improve this. Cell-free DNA (cfDNA) analysis of the pleural fluid may improve MPE detection by identifying tumor-specific DNA even if cytology is negative. In the short-term, we are developing a cfDNA assay to distinguish between MPEs and non-MPEs. In the long-term, we seek utilize this assay to improve MPE detection, treatment selection and outcomes for lung cancer patients.

Long Read Nanopore Sequencing for Rapid Genomic Evaluation of Myeloid Neoplasms

PI: Eric Duncavage, MD
Washington University School of Medicine: Pathology and Immunology

Cancer is a disease of the genome. The diagnosis and management of cancers of the blood including acute myeloid leukemia (AML) are therefore increasingly driven by genomic data. In this pilot study we will use of newly available Oxford Nanopore long read whole genome sequencing (WGS) to generate accurate genomic data in AML patients and determine the clinical suitable of the technology. Ultimately long read sequencing may improve detection of structural variants (chromosomal translocations, amplifications, and deletions) present in most AML patients and has the potential to decrease the cost and turn-around time of WGS, therefore increasing patient accessibility.

Sphingosine-1-phosphate Signaling in Parturition

PI: Antonina Frolova, MD, PhD
Washington University School of Medicine: Obstetrics and Gynecology

Preterm birth affects 10.6% of livebirths or ~15 million babies worldwide each year and results in child mortality or lifelong morbidity. We have only a few, low-efficacy therapeutics to prevent this devastating outcome, in part due to our insufficient knowledge of the mechanisms responsible for preterm labor. Our preliminary work has identified sphingosine-1-phosphate (S1P), as a potential new target for preterm birth prevention. The S1P pathway appears to be activated upstream of the uterine contractile machinery activation and, therefore, would be a novel target for drug development to optimize uterine contractility and improve obstetric outcomes for millions of women and babies.

Evaluating New Methods for Rapid Diagnosis of Acute Kidney Injury in Critically Ill Patients

PI: Joseph Gaut, MD, PhD
Washington University School of Medicine: Pathology and Immunology

Critically ill patients who develop acute kidney injury (AKI) have prolonged hospitalization and increased rates of chronic kidney disease and death. Current AKI diagnosis methods are non-specific and unable to identify kidney damage quickly enough for treatments to be effective. We developed new methods to quantify the kidney specific enzyme, MIOX, and its substrate, myo-inositol, in plasma and urine. This proposal will evaluate MIOX and myo-inositol as rapid and specific AKI biomarkers in critically ill patients. Long-term, the study has potential to transform care of AKI patients by allowing for initiating methods to prevent kidney damage and targeting new drug therapies for AKI.

Medication-assisted Psycotherapy: Using Ketamine-enhanced RODBT to Target Neural and Behavioral Mechanisms of Action in Emerging Adults with Moderate to Severe Depression

PI: Kirsten Gilbert, PhD
Washington University School of Medicine: Psychiatry

Around 30% of depressed individuals do not respond to treatment (Treatment Resistant Depression; TRD). This study targets tendencies of rigidity and perfectionism often seen in TRD using a new treatment that combines fast-acting medication (ketamine) with longer lasting skill building via therapy (Radically Open Dialectical Behavior Therapy) in young adults with TRD. Given the current mental health crisis, only worsened by COVID-19, the current project aims to develop a cutting-edge, powerful and durable treatment for TRD that will provide free treatment for participants (short-term), and long term, could provide a new treatment leading to neural change and decreased suffering in TRD.

Repurposing Hyperlipidemia Drug Fenofibrate for the Treatment of Retinitis Pigmentosa

PI: Jaya Gnana-Prakasam, PhD
Saint Louis University School of Medicine: Ophthalmology

The proposed study evaluating the utility of fenofibrate drug for Retinitis Pigmentosa in mouse models will have a significant impact on RP patients with potential for immediate clinical utility as fenofibrate is already an FDA approved drug commonly used in the clinic to treat hyperlipidemia. Due to high prevalence, Retinitis Pigmentosa represents a major economic burden not only due to the medical costs involved but also cause working age adults are mostly affected by vision threatening Retinitis Pigmentosa and hence repurposing the fenofibrate drug for RP treatment will have long-term community benefits.

Clonal Hematopoiesis in Heart Transplant Recipients

PI: Lakshmi Gokanapudy Hahn, MD
Washington University School of Medicine: Department of Pediatrics, Division of Cardiology

Heart transplantation is a treatment for patients with end stage heart failure. Rejection and complications of immunosuppression such as malignancy and infection are the major causes of death. Clonal hematopoiesis occurs when a blood stem cell acquires changes in its genes that confer a survival advantage. The goal of the project is to define the clinical relevance of CH on heart transplant outcomes including rejection and graft failure and to gain mechanistic insights. Establishing CH as a modifiable risk factor for transplantation can impact recipient selection and allow us to develop personalized immunosuppression plans that improve short and long term transplant patient survival.

Development of a School-based Care Coordination Service Model to Support Youth with Asthma

PI: Kelly Harris, PhD
Washington University School of Medicine: Occupational Therapy

This proposal is a transdisciplinary mixed methods study with an overall objective to work in collaboration with our partner school district to co-develop a service model with accompanying implementation strategies to facilitate care coordination and communication across medical, school, and home settings. We anticipate that this study will also provide data on how to best implement this service model in the context of the existing constraints. Development of this service model will address identified barriers, improve school-based asthma management, and reduce asthma impact for school aged youth.

The Effects of Improved Sleep on Psychopathogy and Brain Function in School-aged Children

PI: Caroline Hoyniak, PhD
Washington University School of Medicine: Psychiatry

This study explores how improved sleep in the context of a behavioral sleep intervention predicts changes in brain function and co-occurring mental health symptoms in school-aged children. This study will inform our understanding of the effects behavioral sleep intervention, a low-risk and feasible intervention, on child mental health and brain function. Given previous research suggesting as many as 74% of children with sleep disturbances also have mental health symptoms, results may also provide support for the integration of behavioral sleep techniques into ongoing mental health interventions, especially for children with co-occurring sleep and mental health disturbances.

Treatment Decisions and Quality of Life in Patients with Polycystic Ovary Syndrome

PI: Patricia Jimenez, MD
Washington University School of Medicine: Obstetrics and Gynecology

Polycystic ovary syndrome (PCOS) is the one of the most common gynecologic conditions affecting up to 5 million women in the U.S. PCOS can be associated with serious medical conditions such as diabetes, elevated cholesterol, endometrial cancer, and infertility, making appropriate diagnosis and management critical. In this project, we proposed a patient-centered approach for the management of PCOS with the goal of improving health-related quality of life for individuals with PCOS. If successful, this approach could improve the treatment of patients with PCOS leading to improved health and decreased long-term health risks resulting in healthier individuals and communities.

Staphylococcus Aureus Antibody Response in Maternal Infant Dyads

PI: Carol Kao, MD
Washington University School of Medicine: Department of Pediatrics, Division of Infectious Diseases

S. aureus infections cause significant morbidity and mortality in children and adults, resulting in substantial healthcare costs. S. aureus has continuously evolved to evade antibiotic therapy and a universal vaccine is the most dependable solution. Efforts to develop a vaccine have so far been unsuccessful, in part due to a limited understanding of human immunity to S. aureus. Our objective is to comprehensively characterize the repertoire of maternally-derived antibodies against S. aureus at birth using cutting-edge immunology. Findings from this study will inform novel vaccine development against S. aureus, which has significant potential benefit to patients and the worldwide community.

Deep Learning to Jointly Align, Impute, and Transform EHR Databases

PI: Christopher King, MD, PhD
Washington University School of Medicine: Anesthesiology

This proposal tests and extends methods for automatically merging two health record databases where most of the variables do not have a known matching; for example, when the variable names are ambiguous. Currently, this is an expensive and error prone manual process when merging electronic health records. Automated methods for database merging are important to allow less-resourced health systems to submit data to collaborative projects like COVID-19 registries and to use artificial intelligence tools developed by those consortia. In this project, our methods need more testing in real data to tune them and understand their performance.

Determine whether CD62L Defines a Functionality Distinct Subset of Human Memory B Cells

PI: Brian Laidlaw, PhD
Washington University School of Medicine: Department of Medicine, Division of Allergy and Immunology

Memory B cells are essential for the establishment of protective immunity following SARS-CoV-2 vaccination. However, breakthrough infection still occurs in individuals with SAR-CoV-2-specific memory B cells. We hypothesize that the phenotype of the memory B cell response induced following vaccination is an important factor in determining an individual’s susceptibility to re-infection. In this study, we will investigate how the composition of memory B cell response shapes the ability of these cells to protect upon SARS-CoV-2 re-infection. This work will provide important insight into biomarkers that may indicate the susceptibility of an individual to breakthrough infection.

Neuromodulation using Vagus Nerve Stimulation following Ischemic Stroke as Therapeutic Adjunct

PI: Osvaldo Laurido-Soto, MD
Washington University School of Medicine: Neurology

Stroke is the second leading cause of death. AIS due to LVOs account for the most severe outcomes. Neuroinflammation exacerbates brain injury in AIS. We propose to study a drug-free approach to reducing neuroinflammation after stroke, using non-invasive taVNS stimulating the vagus nerve to reduce inflammation, a method proven effective in other conditions. We will pilot a randomized trial of taVNS vs. best medical treatment to determine if taVNS can reduce inflammatory biomarkers. Short-term, we will define the impact that taVNS has on inflammation; long-term, we will perform a randomized clinical trial to determine if taVNS can reduce disability and improve outcome following AIS.

Free to Flex: Evaluation of a YMCA-Based Initiative to Support Physical Activity among Transgender and Gender Diverse Youth in St. Louis

PI: Whitney Linsenmeyer, PhD
Saint Louis University Doisy College of Health Sciences: Nutrition and Dietetics

Free to Flex is a proposed YMCA-based initiative to support physical activity and well-being among transgender and gender diverse (TGGD) youth and their families in St. Louis. Elements will include shifts within the YMCA environment (i.e. gender-inclusive policies, signage, and staff training) and unique programming (i.e. personal training, cooking classes, and a clothing exchange). This project is a collaboration between the YMCA, TransParent, Saint Louis University, and the Washington University Transgender Center at St. Louis Children’s Hospital. An advisory group of TGGD youth, parents, and community leaders will inform all stages of the development, implementation, and research.

Define the Utility of Autophagy-Associated ATG16L1 T300A Genotype in Prognostic Stratification of Hepatocellular Carcinoma

PI: Changqing Ma, MD, PhD
Washington University School of Medicine: Pathology and Immunology

An unmet clinical need in hepatocellular carcinoma (HCC) management is the accurate prediction of prognosis. We showed that the ATG16L1 T300A SNP variant, a major Crohn’s disease susceptibility allele, is orrelated with survival in cancer and increased inflammation in tumor microenvironment. We hypothesize that the T300A genotype is associated with increased inflammation in HCC tumor microenvironment and reduced survival. We will test the hypothesis using survival analysis, histology review and spatial transcriptomics of a large HCC cohort. Our analysis will provide a unique opportunity to realize the prognostic value of T300A genotype in HCC and define its impact in tumor microenvironment.

Novel Determinants of Reengagement in HIV Care in Zambia

PI: Aaloke Mody, MD
Washington University School of Medicine: Department of Medicine, Division of Infectious Diseases

People living with HIV (PLWH) frequently transition in and out of care, which can lead to poor outcomes over time. Even when PLWH return to care after loss to follow-up (LTFU), rates of becoming LTFU again in the future are very high due to diverse structural, psychosocial, and health-system barriers. This proposal seeks to examine three novel and underexplored factors-the patient experience when reengaging, barriers to HIV care, and unexpected life events-as critical drivers of whether individuals remain in care after reengagement in Zambia. This proposal will build upon a larger clinical trial planning grant and will leverage existing data from the electronic health record in Zambia.

MAP for Coaches: A Web-Based Musculoskeletal Athletic Injury Prevention Training Course to Increase the Routine use of Neuromuscular Training Warm-Up Programs

PI: Oluwatoyosi Owoeye, MS, PhD, BPT
Saint Louis University Doisy College of Health Sciences: Physical Therapy and Athletic Training

This project has potential for community and economic benefits through the extensive dissemination of the MAP for Coaches towards improving the widespread utilization and maintenance of NMT programs among youth sport coaches. This will subsequently help reduce musculoskeletal injuries and associated consequences and healthcare cost in youth sport communities. The MAP for Coaches is expected to increase the widespread dissemination of injury prevention knowledge and prevention to several coaches in St. Louis and beyond, including coaches in underserved communities, overcoming the barriers associated with in-person gathering and promoting equitable assess to evidence-based information.

Defining Immune Biomarkers of Clinical Response to Neoantigen Vaccines in Metastatic Prostate Cancer Patients

PI: Russell Pachynski, MD
Washington University School of Medicine: Department of Medicine, Division of Oncology

Prostate cancer causes approximately 34,000 deaths per year in the US. Neoantigen vaccines hold promise but have only been tested in a limited number of tumor types. We performed the first trial of these vaccines in metastatic prostate cancer patients, and have recently completed accrual. Here we propose to analyze serial samples collected throughout the trial. Analyses of the induced changes in the tumor microenvironment and immune responses will improve our understanding of the differences underlying responders and non-responders, and could unveil potential mechanisms that lead to new and improved treatments in the future.

Understanding Host-Pathogen Interaction in the Nasal Epithelium during Pregnancy

PI: Arvind Palanisamy, MD, FRCA
Washington University School of Medicine: Anesthesiology

This project will reveal how pregnancy alters susceptibility to respiratory viruses and allow informed risk stratification of pregnant women in future pandemics involving novel viruses. Because pregnant women are typically excluded from new vaccine trials, knowing whether a pregnant woman is vulnerable to a novel infection will be helpful in framing public health policy surrounding vaccine prioritization. Finally, if our studies confirm enhanced innate immunity in the nasal epithelium of pregnant subjects, it will inspire a paradigmatic shift in thinking – away from the conventional dogma of generalized immunosuppression in pregnancy towards organ-specific immune adaptation.

Stakeholders’ Perceptions of Consensus Guidelines about Antibiotics for Asymptomatic Bacteriuria

PI: Mary Politi, PhD
Washington University School of Medicine: Department of Surgery, Division of Public Health Sciences

Doctors often prescribe antibiotics for bacteria in the urine due to changes in urine appearance or odor. Antibiotics are not recommended in these situations and can lead to side effects and antibiotic resistance. Asking older adults and caregivers their thoughts about diagnosis and treatment of bacteria in urine ensures that care communication is clear and responsive to patients’ needs and goals. We will conduct 30 interviews with older adults and caregivers to ask their thoughts about treatment guidelines for bacteriuria in urine. With this data, and data from other work, we can develop patient-friendly interventions to support appropriate antibiotics use for older adults in this context.

Dehyroepiandrosterone (DHEA) Thereapy for Improved Treatment of Dry Eye Disease (DED)

PI: Lixing Reneker, PhD
University of Missouri – Columbia School of Medicine: Ophthalmology

Meibomian gland dysfunction (MGD) is the most common form of dry eye disease (DED), which causes eye discomfort and/or damage to the ocular surface. MGD and DED affect millions of people, particularly women over 50 years old. Sex and sex hormones are known to affect the functions of the meibomian glands, and contribute to the difference in DED prevalence between women and men. The proposed study is to to determine whether sex hormones can be made locally in human meibomian glands from dehydroepiandrosterone, or DHEA, which is a pre-hormone in the circulation that is normally produced by adrenal glands-topical application of DHEA may improve the clinical management of MGD at a low cost.

Multisource Comprehensive Database for Pediatric ECMO Patients

PI: Ahmed Said, MD, PhD
Washington University School of Medicine: Department of Pediatrics, Division of Critical Care Medicine

This project aims to combine patient data from the electronic health records, bedside telemetry, local extracorporeal membrane oxygenation (ECMO) registry with patient outcomes including survival, seizures, electroencephalographic abnormalities, abnormalities on head imaging and functional outcomes at discharge to develop a first-of-its-kind comprehensive ECMO patient database. This database will allow the development of predictive analytic models that truly incorporate the rapidly evolving nature of the patients’ pathology with meaningful neurologic outcomes to guide clinical decision making on ECMO initiation and timing to improve patient outcomes.

Global Metabolomics Analysis for Biomarker Discovery and Immunomodulatory Therapy for Glaucoma

PI: Pawan Kumar Singh, PhD
University of Missouri – Columbia School of Medicine: Ophthalmology

Glaucoma is a leading cause of blindness globally after cataracts. Vision loss in glaucoma mainly occurs due to retinal ganglion cell death and currently, there are no treatments available to prevent this. Similarly, there is no diagnosis available for early detection of glaucoma and patients are mainly screened for elevated intraocular pressure (IOP). IOP is the only modifiable risk factor for this disease, however, glaucomatous damage could happen even without IOP elevation, or in people whose IOP is controlled with medication. This project will use a novel metabolomics approach to identify biomarkers that could be used for early diagnosis and therapy for this blinding disease.

Precision Modeling of Genetic Variants in Atypical Diabetes

PI: Stephen Stone, MD
Washington University School of Medicine: Department of Pediatrics, Division of Endocrinology and Diabetes

Currently, only a small percent of patients who undergo genetic testing for atypical diabetes receive a definitive diagnosis. Many patients, instead, receive genetic results which their doctors are unable to interpret. Our long-term goal is to develop a tool that can provide clarity to these previously unclear genetic results. We plan to use new advances to stem cell and gene editing technologies which have recently made this possible. In this proposal, we aim to lay the foundation for future ambitious projects taking us closer to our goal. Specifically, we will study known genetic causes of diabetes, and measure how different platforms can capture their dysfunction at a cellular level.

Biomarkers for Epilepsy Prediction in Very Preterm Infants with Intraventricular Hemorrhage

PI: Regina Triplett, MS, MD
Washington University School of Medicine: Neurology

Epilepsy is diagnosed by the occurrence of seizures and treated with medications to stop seizures. Epilepsy prevention requires a better understanding of the period before seizure pathways become established in the brain among patients at high risk. Infants born very preterm are at high risk of brain injury, which puts them at high risk of epilepsy. This project will use advanced electroencephalography (EEG) technology to study early electrical brain activity patterns from preterm infants before seizures start. The goal of this study is to predict epilepsy in preterm infants, allowing future studies to evaluate strategies for preventing epilepsy in preterm infants and other groups at risk.

Exercise Capacity and Skeletal Metabolism in Post-COVID Cardiovascular Syndrome

PI: Amanda Verma, MD
Washington University School of Medicine: Department of Medicine, Division of Cardiology/Cardiovascular Diseases

People who had COVID-19, including those with only mild disease, often experience fatigue, dyspnea, and physical activity intolerance for months after the acute phase of infection. Results from cardiopulmonary exercise testing in people with PASC suggest their physical activity intolerance is primarily related to alterations in skeletal muscle, rather than cardiopulmonary dysfunction. The goal of this proposal is to evaluate putative skeletal muscle factors that can cause physical activity intolerance in PASC. In addition, we will evaluate the effect of a novel therapeutic intervention (treatment with a sodium-glucose cotransporter inhibitor) and putative underlying mechanism(s) of action.

Immune Response to COVID-19 Omicron Variant mRNA Boosting Vaccincation in Patients with Primary Antibody Deficiency (PAD) Syndromes

PI: Ofer Zimmerman, MD
Washington University School of Medicine: Department of Medicine, Division of Allergy and Immunology

Patients with primary antibody deficiency syndromes (PAD) are more susceptible to infection and have weakened immune responses to vaccination. We recently showed that the response of these patients to COVID-19 vaccination is attenuated. Emerging COVID-19 variants, such as Omicron, can decrease the protection conferred by prior COVID-19 vaccination or infection. New variant-specific vaccines will be available soon. Our study will evaluate immune responses to the new variant specific booster of patients with PAD disorder to determine their possible short- or long-term benefit. We will also test if genetic changes in these patients can predict immune responses to COVID-19 vaccination.