CINCINNATI—The University of Cincinnati’s (UC) Center for Clinical and Translational Science and Training (CCTST) has awarded 15 grants to researchers at UC and Cincinnati Children’s Hospital Medical Center.
Of the awards, 12 are one-year pilot grants intended to support novel T1 translational research projects designed to bring discoveries from the bench to the bedside. The remaining three are multi-year career development awards for junior faculty members.
Funds for the awards were made possible through the university’s institutional Clinical and Translational Science Award, a five-year, $23 million National Institutes of Health grant awarded in 2009 that supports programs at the CCTST. Established in 2005 as a collaborative effort among UC, Cincinnati Children’s Hospital Medical Center, University Hospital and the Cincinnati Department of Veterans Affairs Medical Center, the CCTST is a research resource and "academic home” for clinical and translational scientists and programs.
Below is a complete list of grant winners and research projects.
Using topical capsaicin to limit reperfusion injury
Principal investigator Neal Weintraub, MD, professor and chief of the cardiovascular diseases division at UC, will partner with Keith Jones, PhD, of UC’s pharmacology and cell biophysics department, to determine if capsaicin applied to the abdomen during brachial artery ischemia will reduce injury to vascular lining dysfunction caused by reperfusion injury. Their research could lead to development of a simple, safe and widely applicable approach to improving outcome in patients with myocardial infarction. Early results of this work appeared in September 2009 in the journal Circulation. Read more.
Antidepressant therapy in breastfeeding mothers
Principal investigator Laurie Ann Nommsen-Rivers, PhD, a neonatology researcher at Cincinnati Children’s, will partner with co-investigators Nelson Horseman, PhD, and Karen Gregerson, PhD, both of UC, to study whether or not antidepressant medications interfere with a mother’s ability to make breast milk. The team will also determine whether or not breastfeeding mother respond different to antidepressant medicines, as compared to mothers who are not breastfeeding? Knowledge gained from this research will contribute to more optimal care for breastfeeding mothers suffering from depression. Work recently published by Horseman indicates that women who take a commonly used form of antidepressant drugs may experience delays in lactation after giving birth and may need additional support to meet their breast-feeding goals. Read more about this study.
Development and validation of serum VEGFD as a clinical diagnostic test in lymphangioleiomyomatosis
Principal investigator Lisa Young, MD, a pulmonologist at Cincinnati Children’s, will partner with UC’s Frank McCormack, MD, to determine the accuracy of testing levels of vascular endothelial growth factors for a diagnosis of lymphangioleiomyomatosis (LAM) and whether this blood test can be used to monitor response to treatment. LAM is a lung disease that usually requires surgical lung biopsy for diagnosis. Read more on recent LAM research.
Novel translational therapies for congenital PAP
Principal investigator Bruce Trapnell, MD, pulmonary biologist at Cincinnati Children’s, will partner with Punam Malik, MD, also of Cincinnati Children’s, to study genetic causes for pulmonary alveolar proteinosis, a disease in children caused by accumulation of surfactant protein that reduces lung function. Tests have been developed to identify children with this disease and determine if it is caused by mutations of the gene for a molecule on macrophages functioning as a receptor for a bone marrow stimulant. Results from this grant will provide preliminary data to apply for funds from the National Institutes of Health and to translate this into a human gene therapy. Trapnell first identified PAP and reported his findings in the Nov. 24, 2008, issue of the Journal of Experimental Medicine. Read more.
Telomerase: a therapeutic target in pediatric brain tumors
Principal investigator Rachid Drissi, PhD, a hematology oncology research at Cincinnati Children’s, will partner with Cincinnati Children’s researchers Timothy Cripe, MD, PhD, and Maryam Fouladi, MD, to improve efficacy of radiation while minimizing its side effects. The team will use radiation concurrently with a compound that sensitizes cancer cells to radiation therapy. This combination therapy is expected to be more effective at lower radiation doses and therefore will minimize its side effects.
Clinical diagnostics for pediatric cardiomyopathy
Stephanie Ware, MD, PhD, a researchers in molecular cardiovascular biology and human genetics at Cincinnati Children’s, will partner with Cincinnati Children’s researchers Lisa Martin, PhD, and Curtis Jamison, PhD, to study the genetic basis of pediatric cardiomyopathy. This heterogeneous genetic disease has high morbidity and mortality in which children often present with fulminant disease leading to death or transplant. There is an opportunity to make a large impact on anticipatory prevention, surveillance, early management, and disease course based on identifying the disease-causing and disease-associated genetic risk factors. The long term goal of this project is to identify the genetic basis of pediatric cardiomyopathy using novel genomic technologies in patients with clinically well defined subtypes of cardiomyopathy.
Novel approaches to MTS; augmentation of innate immunity
UC pulmonologist Frank McCormack, MD, will partner with Cincinnati Children’s researcher Bruce Trapnell, MD, to study a treatment for drug-resistant tuberculosis. Lung infection with tuberculosis is one of the leading causes of death worldwide. The ability of these organisms to become resistant to antibiotics and to evade killing by the major defensive cells in the lung thwart efforts to control this 10,000-year-old public health problem. This project will explore the utility of an FDA-approved drug called keratinocyte growth factor in the treatment of tuberculosis and related organisms. Data collected during this project will provide the foundation for trials of this growth factor in patients with drug resistant tuberculosis and tuberculosis-like organisms.
Norovirus P particle, a multifunctional platform for vaccine development
Principal investigator Ming Tan, PhD, an infectious diseases researcher at Cincinnati Children’s, will work with co-investigator Xi Jiang, PhD, of Cincinnati Children’s, to develop a subunit of norovirus (the virus causing infectious diarrhea) into a useful platform for vaccine production. The subunit appears to offer a flexible, efficient and low-cost strategy for novel vaccine development to improve human health.The subunits are easily produced in E. coli, stable, and highly immunogenic and bind to viral ligand. In addition, viral protein can be easily inserted onto the surface of the subunit, greatly enhancing the immune response of the inserted antigens. The application of the subunit as a carrier for antigen presentation will be studied in this proposal as a novel platform for vaccine development. Our goal is to commercialize the subunit for a broad application in biomedical sciences.
Systems biological prediction of combinational cancer therapeutics
Principal investigator Bruce Aronow, PhD, biomedical informaticians at Cincinnati Children’s, will work with co-investigator Anil Jegga, DVM, and many others at UC and Cincinnati Children’s to form the Cincinnati Center for Predictive and Combinatorial Cancer Therapeutics. The goal of the Center is to discover and predict the most effective cancer therapeutic agents for individual patients. The center will focus on identifying combinations of therapeutic agents that act synergistically against specific cancers and that minimize toxicity to patients. This project will build a database and collect data that will enable many different investigators to work together to identify powerful new therapeutic strategies that can be tested preclinically and for the testing and discovery of entirely new therapeutic regimens in clinical trials.
SapC-DOPS agents: Imaging and therapeutics in arthritis
Principal investigator Sherry Thornton, PhD, rheumatology researcher at Cincinnati Children’s, will work with co-investigator Xiaoyang Qi, PhD, of Cincinnati Children’s, to study early detection of rheumatoid arthritis. Rheumatoid arthritis affects 1 percent of the population. Early detection and intervention are the best hope for preservation of joint mobility and function. Currently, assessment of disease onset and progression relies on physician assessment, which is highly variable. This proposal will examine a novel method for visualization of arthritic disease using an agent, SapC-DOPS-CVM, with high affinity for injured cells. Results from these studies may provide a novel method for tracking cells involved in inflammatory processes during arthritis, which may easily be translated into the clinic.
Real-time nitric oxide measurements as a predictor of AV fistula maturation
Principal investigator Prabir Roy-Chaudhury, MD, PhD, nephrologists at UC, will work with co-investigators Elaine Urbina, MD, of Cincinnati Children’s, and Mark Meyerhof, PhD, of the University of Michigan to develop a way to determine fistula failure. There are currently 350,000 patients on hemodialysis in the United States who require some sort of vascular access for dialysis. The best form of vascular access is a connection between the artery and vein in the forearm, called an AV fistula. Unfortunately these fistulae often get narrowed and then clogged up due to poor production of a molecule called nitric oxide. The purpose of this proposal is to test out a new technique to measure nitric oxide in the blood, in order to identify which fistulae are likely to fail.
Principal investigator James Mulloy of Cincinnati Children’s will work to develop a Xenograft Core. Animal models of cancer are critical for testing novel drugs. The xenograft model, whereby human tumors are grown in immune-deficient mice, is the preclinical modality used by clinical centers and pharmaceutical companies for screening new agents and novel combinations of drugs. This Xenograft Core builds on our extensive experience and extends our capabilities to bridge clinical scientists with basic scientists for mouse modeling of human cancer, focusing on lung cancer, neural/brain cancer and leukemia. The Xenograft Core will ensure the local infrastructure is available for the Academic Health Center as we move towards increased integration of translational and basic science.
KL2 Career Development Awards
Defining axonal injury in mild traumatic brain injury
Lynn Babcock Cimpello, MD, Emergency Medicine, Cincinnati Children’s
Traumatic brain injuries are the leading cause of disability in children. Even though the majority of these are defined as "mild” traumatic brain injury, there is evidence that between 15 and 50 percent of children with mild traumatic brain injury will have poor functional outcomes; however, there remains no reliable tool for clinical outcome prediction. The goal of Babcock’s work is to find and validate an accurate and objective marker of injury to the brain following minimal traumatic brain injury that correlates with both acute injury severity and long-term functional outcomes and that is readily available to the clinician in the emergency department.
Psychogenic tremor: functional magnetic resonance study on emotional processing
Alberto Espay, MD, Neurology, UC
Espay will work to identify aberrant neural circuits in patients with psychogenic tremor, when compared with patients with essential tremor and healthy subjects, in response to emotional processing stimuli, which will allow distinction between these groups of subjects and help in guiding and monitoring future therapeutic interventions.The rationale underlying this project is that, despite the high prevalence of and disability in psychogenic tremor, its pathophysiology remains poorly understood and, as a consequence, this lack of basic knowledge leads to ineffective treatment strategies that do not alleviate the great burden of this disease to the individual and society.
Molecular mechanisms of regenerative wound repair
Sundeep Keswani, MD, Pediatric and Thoracic Surgery, Cincinnati Children’s
The overall goal of this work is to define the anti-inflammatory cytokine IL-10-mediated molecular mechanisms permissive of a regenerative wound healing phenotype.This will enable scientists to develop novel therapeutic strategies to recapitulate this regenerative response by the over-expression of IL-10 in response to injury in postnatal tissues. If the goals of this work are realized, there may be significant implications, not only for treatment of wounds, but also for a broad range of diseases and conditions characterized by excessive fibroplasia, including pulmonary fibrosis, hepatic cirrhosis, intra-abdominal adhesions, burn scar and scleroderma.