Announcements Funding CTRFP Awardees ICTS News

ICTS Announces 2024-2025 CTRFP Awardees

(1st row, left to right) Samantha Adamson, MD, PhD; David Brogan, MD, MSc; Siyan Cao, MD, PhD; Brian DeBosch, MD, PhD; Stefanie Geisler, MD; Sarah Greene, MD, PhD (2nd row, left to right) Anuja Java, MD; Jesus Jimenez, MD, PhD; MohammadMehdi Kafashan, PhD; Alfred Kim, MD, PhD; Jennie Kwon, DO, MSCI; Kenan Li, PhD; Jacqueline Limberg, PhD (3rd row, left to right) Chongliang Luo, PhD; Laura McPherson, PT, DPT, PhD; Jeffrey Miner, PhD; Mary Mullen, MD; Christine O'Brien, PhD; Susan Perlman, PhD; Margaret Reynolds, MD

Washington University Institute of Clinical and Translational Sciences (ICTS) and The Foundation for Barnes-Jewish Hospital awards 20 investigators as part of the 17th 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 2024, awards were considered across three project categories: clinical/translational, community-engaged research, and biostatistics, epidemiology, and research design.

This year the CTRFP received around 70 letters of intent and awarded approximately $1M 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 2024 awardee cohort effective March 1, 2024.

Metabolomic Effects of SGLT2 Inhibition and Insulin Withdrawal in People with Type 1 Diabetes

PI: Samantha Adamson, MD, PhD
Washington University School of Medicine: Department of Medicine, Division of Endocrinology, Metabolism & Lipid Research

Patients with type 1 diabetes (T1DM) would greatly benefit from adjunct therapies (other than insulin) to control blood sugars and prevent complications. SGLT2 inhibitors are oral medications effective for treating type 2 diabetes; however, because these drugs are associated with diabetic ketoacidosis (DKA), they have not been used in patients with T1DM, who are prone to DKA when blood sugars are high without sufficient insulin. Evaluating SGLT2i-mediated changes in plasma metabolites in patients with T1DM in the basal state and during insulin withdrawal will provide insight into mechanisms of increased DKA risk and provide advance understanding of how these drugs could be safely used to treat T1DM.

Quantification of Serum Neurofilament Light Chain in Peripheral Nerve Injury

PI: David Brogan, MD, MSc
Washington University School of Medicine: Department of Orthopaedic Surgery, Division of Hand and Microsurgery

Diagnosis of peripheral nerve injury and compression can be challenging even for the most experienced clinician. Assessment of nerve damage is currently based on a variety of indirect parameters including physical exam signs, history and electrodiagnostic tests. The lack of a gold standard measure for evaluation and prognostication of peripheral nerve injury can lead to delayed or sub-optimal treatment. This proposal will examine a potential biomarker of nerve injury to aid in diagnosis as well as prognosis. The future application of this study is earlier identification of peripheral nerve injury from a wide array of practitioners. This could facilitate rapid diagnosis and faster referral.

Molecular Signatures of IL-23-Responsive Cells as Therapeutic Biomarkers for Anti-IL-23 Therapies in Crohn’s Disease

PI: Siyan Cao, MD, PhD
Washington University School of Medicine: Department of Medicine, Division of Gastroenterology

This proposal aims at identifying therapeutic biomarkers that predict response to anti-interleukin 23 (IL-23) antibodies, one of the mainstream treatments for Crohn’s disease (CD). In the short term, this study may guide the rational use of anti-IL-23 therapies and prevent complications in CD patients. Longer term benefits of the study will advance the precision medicine approach for treatment in inflammatory bowel disease and beyond.

Predictors of Childhood Obesity and Fatty Liver Disease Through Early-Life Stool Virome and Metagenomics

PI: Brian DeBosch, MD, PhD
Washington University School of Medicine: Department of Pediatrics, Division of Gastroenterology, Hepatology & Nutrition

This project aims to identify predictors of obesity and its metabolic complications in otherwise healthy children using virome and metagenomic data from the first stools in life. If we are successful, the data will justify two key next steps. First we will have newly discovered information to then study how and why these virome or metagenomic agents might interact with the host to cause metabolic disease in children. Second, we will validate the predictive findings in subsequent patient cohorts. Our long term goal is to develop early life stool clinical biomarkers to predict obesity and its complications.

Sphingolipidomics to Identify Small Fiber Neuropathy Endotypes

PI: Stefanie Geisler, MD
Washington University School of Medicine: Department of Neurology

Patients with small fiber neuropathy (SFN) suffer from burning pain, tingling, numbness, fatigue, myalgias, and muscle cramps. There currently are no effective treatments for SFN. A major impediment for developing effective SFN therapies are the significant between-patient differences of the disease, which may be due to different mechanisms leading to SFN. We recently identified 3 distinct SFN subtypes. This proposal aims to identify biomarkers for the SFN subgroups, which may lead to the development of personalized, targeted therapies.

Developing Diagnostics for Onchocerciasis

PI: Sarah Greene, MD, PhD
Washington University School of Medicine: Department of Pediatrics, Infectious Diseases

Onchocerciasis is the 2nd leading infectious cause of blindness worldwide, with > 200 million people at risk of infection in Africa. The World Health Organization coordinates efforts to eliminate this infection, but improved diagnostic tests are needed to map infected areas and assess program success. We used a novel approach for protein analysis of parasite reproductive tissue isolated by laser capture from biopsies of infected patients to identify candidate biomarkers for diagnosis of active infections. We identified and will further evaluate 2 potential biomarkers. Further studies of these and additional biomarkers identified in this project may lead to new diagnostic tests needed for elimination of this disease.

Role of Complement in Hypertensive Disorders of Pregnancy

PI: Anuja Java, MD
Washington University School of Medicine: Department of Medicine, Division of Nephrology

Preeclampsia is a pregnancy complication that causes high blood pressure, kidney and heart failure. It closely resembles atypical hemolytic uremic syndrome (aHUS), a disease that occurs due to an overactive complement system due to genetic mutations in complement proteins. We speculated that an overactive complement system due to genetic mutations may also lead to preeclampsia. In prior work, we conducted genetic testing in 65 preeclampsia patients and have identified 2 mutations in a not-well-studied complement protein, CSMD3. To establish if CSMD3 is a risk factor for preeclampsia, we will conduct genetic sequencing in a 2nd cohort of patients and will study the effects of CSMD3 in a mouse model.

Advances in the Diagnosis of Immune Checkpoint Inhibitor Myocarditis

PI: Jesus Jimenez, MD, PhD
Washington University School of Medicine: Department of Medicine, Cardiovascular Division

Immune checkpoint inhibitors, which work by activating the immune system to target and kill cancer cells, are increasingly being used to treat patients. Unfortunately, these drugs may cause serious side effects in the heart including life-threatening myocarditis. The current approach for diagnosis is to obtain an endomyocardial biopsy. This proposal seeks to perform the first-in-patient CCR2 molecular imaging to identify patients with immune checkpoint inhibitor myocarditis. The use of noninvasive CCR2 radiotracer imaging may identify inflammatory cells to improve diagnosis of immune checkpoint inhibitor myocarditis and has the potential to track response to therapy in the long-term.

Sleep and Cognition Markers for Early Prediction of Antidepressant Response to Repetitive Transcranial Magnetic Stimulation

PI: MohammadMehdi Kafashan, PhD
Washington University School of Medicine: Department of Anesthesiology

Despite the efficacy of repetitive transcranial magnetic stimulation (rTMS) in alleviating symptoms in patients with Treatment-Resistant Depression (TRD), there are no objective prognostic markers that can predict who will most likely benefit from this intervention. This study will be the first attempt at investigating sleep EEG data, cognitive, and clinical outcomes throughout the full index course of rTMS for TRD. A better understanding of the underlying mechanisms by which rTMS impact sleep may provide innovative prognostic targets for the facilitating an antidepressant response and addressing cognitive dysfunction in this vulnerable population.

Biomarker Utility and Functional Impact of Cell-bound Complement Activation Products in Human Systemic Lupus Erythematosus

PI: Alfred Kim, MD, PhD
Washington University School of Medicine: Department of Medicine, Division of Rheumatology

Lupus nephritis (LN) possesses high rates of morbidity and mortality due to the activation of an inflammatory process called the complement cascade. A diagnosis of LN requires a biopsy, as lab tests are non-specific. Complement activation also confers functional changes to immune cells that may drive worsening disease. We will examine the utility of novel tests measuring complement activation products found on immune cells for LN. Furthermore, we will determine how complement activation can drive pathogenic functional signatures in LN immune cells. This will enable us to identify novel biomarkers for LN and specific cellular targets for therapies that can improve treatment response.

Characterizing the Genetic and Spatial Dynamics Of Pseudomonas Aeruginosa Strains within the Acute Healthcare Setting

PI: Jennie Kwon, DO, MSCI
Washington University School of Medicine: Department of Medicine, Division of Infectious Diseases

Our previous work has implicated sink drains as a persistent reservoir for Pseudomonas aeruginosa (PSAR). However, the extent of PSAR drain colonization and how often these strains contribute to hospital-acquired infections (HAIs) is less understood. We propose a multi-setting, longitudinal sampling of PSAR in sink drains in the healthcare setting to characterize the geographic and resistance patterns of PSAR. Utilizing whole-genome sequencing, we will determine the contribution of sink drain reservoirs to HAIs and antibiotic resistance gene acquisition and loss. Ultimately, this data will inform the necessity and direction of future remediation strategies in different healthcare areas.

Geospatial Analysis of Accessibility and Sociodemographic Influence on Dialysis Treatment in End-Stage Renal Disease Patients

PI: Kenan Li, PhD
Saint Louis University College for Public Health and Social Justice: Epidemiology and Biostatistics

This project aims to analyze ESRD patient behavior and healthcare accessibility using human mobility data. It will pinpoint disparities in healthcare access, socioeconomic factors influencing dialysis modality choice, and neighborhood impacts on ESRD causes. Short-term benefits encompass the creation of targeted interventions and policies to address identified challenges, such as transportation support programs. Long-term benefits will enhance the quality of life for ESRD patients, by addressing the root causes of ESRD by improving access to preventive healthcare and nutritious food, and ultimately preventing the onset and progression of ESRD.

Novel Treatment for Brain Insulin Resistance and Hypoperfusion In Obesity

PI: Jacqueline Limberg, PhD
University of Missouri – Columbia: Division of Food, Nutrition & Exercise Sciences (FNES)

Obesity accelerates brain aging and increases the risk of cerebrovascular disease and related cognitive decline. We will determine the effect of a novel therapeutic, intranasal insulin, on cerebral blood flow and reactivity in younger adults with obesity. We will utilize MRI technology to assess cerebrovascular perfusion in adults with obesity and associated insulin resistance. We hypothesize intranasal insulin improves cerebral perfusion at baseline and in response to a metabolic challenge in adults with obesity. These proof-of-concept studies will provide the basis to develop future novel therapeutic approaches in adults with obesity.

Canonical Variate Regression for Unified Correlation Analysis of Multi-omics Data and Prediction of Cancer Survival Outcome

PI: Chongliang Luo, PhD
Washington University School of Medicine: Department of Surgery

Patient-level cancer survival may be predicted based on multiple sets of omics data (e.g. copy number variation and gene expression, metabolomics and lipidomics), besides the clinical data. Multi-omics data are often correlated and high-dimensional. It is of interest to learn a correlation structure between the sets of multi-omics predictors as well as optimize the prediction. I will use a statistical method called canonical variate regression (CVR) to bridge the correlation structure and the clinical prediction. The performance of the methods will be demonstrated by simulated and public data(e.g. the METABRIC study).

Subclinical Pathophysiology of Voluntary Motor Processing in People With Multiple Sclerosis

PI: Laura McPherson, PT, DPT, PhD
Washington University School of Medicine: Department of Neurology

Multiple sclerosis (MS) damages the central nervous system (CNS), impairing its control of the body’s systems. Disability can develop from both periodic relapses and gradual progression of symptoms over time. MS drugs reduce relapse frequency, but none effectively prevent or slow progression. When patients show progressive symptoms, much CNS damage has already occurred. Our eventual goal is to detect disease progression before symptoms appear. This would be critical for rapid testing of new drugs and for delivering them early to prevent more damage. As a first step, our study will see if our novel measure of CNS motor processing detects changes in MS patients who do not yet have disability.

Improved Diagnosis of Collagen IV-Associated Nephropathies

PI: Jeffrey Miner, PhD
Washington University School of Medicine: Department of Medicine, Division of Nephrology

Chronic kidney disease (CKD) is a global health problem. Some forms of CKD are inherited, but genetic variants found by routine testing are not always clearly disease-causing (pathogenic). This is especially true for collagen IV gene variants, which are quite common in humans (~1% frequency). We are developing a new way to define which ColIV variants are pathogenic so that patients who carry them can have a definitive genetic diagnosis. This will be valuable for 1) determining what treatments would be best for them; and 2) providing their potentially affected family members a way to screen for kidney disease risk and then take actions that are likely to improve their own health outcomes.

Optimizing a Biomarker of Response to Therapy in High-grade Serous Ovarian Cancer

PI: Mary Mullen, MD
Washington University School of Medicine: Department of Obstetrics & Gynecology, Division of Gynecologic Oncology

Current strategies to predict response to drugs commonly used to treat ovarian cancer are not very accurate. This is a problem because some patients don’t receive drugs that might help them. Conversely, other patients receive drugs that won’t kill their tumors but may cause bad side effects. Our lab developed a new strategy that more accurately predicts tumor response to one type of drug. Here, we will further improve our strategy and test its ability to predict response to another type of drug. In the long term, our work will help clinicians give patients the most effective therapy and minimize unnecessary drug side effects.

Development of a Low-Cost Light-Based Cervical Mucus Assessment Tool for Preterm Birth Diagnosis

PI: Christine O’Brien, PhD
Washington University School of Engineering: Department of Biomedical Engineering

Researchers have identified that the cervical mucus (CM) of patients at high risk for preterm birth (PTB) is susceptible to the passage of microbes, and is significantly more stretchy and hydrated than CM from healthy patients. Quantitative assessment of CM could serve as a biomarker for PTB risk, but the standard tools used for measurements are expensive and labor intensive which prevents clinical translation. We propose to develop a low-cost, light-based tool that can quantify CM properties at the point-of-care. This tool could be used to identify patients at high risk of PTB and help us to understand when, why, and how some patient’s CM changes during pregnancy which is currently unknown.

Examining the Role of Pain in the Link Between Early Childhood Adversity and Psychopathology

PI: Susan Perlman, PhD
Washington University School of Medicine: Department of Psychiatry

The overarching goal of our project is to examine the roll of physical pain in the established trajectory from early life adversity to psychiatric disorder. We will use a novel pain task to examine the impact of parental support on pain modulation in middle childhood as our existing sample. This sample/pain task s is well-characterized for early life adversity, and transitions into adolescence when both chronic pain and psychiatric disease often receive a first diagnosis. Support for our model may indicate that interventions that increase parental support might decrease both pain and psychopathology in childhood while also pointing to symptoms of pain as a potential early indicator of psychopathology onset.

Phenotype After Refractive Surgery for Autism Spectrum Disorder

PI: Margaret Reynolds, MD, MSCI
Washington University School of Medicine: Department of Ophthalmology and Visual Sciences

Autism spectrum disorder (ASD) is associated with impaired social communication. 1/4 of ASD children require glasses; however, 1/3 cannot tolerate spectacles. For these children, we perform refractive surgery to improve visual acuity. After surgery, children can have improved behavior. In this study, we will use surveys to examine behaviors pre-and post-surgery. Understanding behavior changes may inform the role of visual acuity in ASD. If ASD phenotype improves, pediatric refractive surgery could be easily disseminated as thousands of centers perform this surgery on adults. Future applications will examine visual improvement as an intervention and brain-based changes via brain imaging (MRI).