10 Apr CTSI Announces 2014 Pilot Grant Awardees
The CTSI scientific community has come together once again to work in partnership in multidisciplinary research teams to discover clues that will lead to better treatments and cures for today’s medical threats. CTSI seeks to cultivate inter-institutional and interdisciplinary collaboration between clinical and basic biomedical scientists, social scientists, ethicists, engineers, biostatisticians, informatics specialists, and all members of clinical health care delivery teams.
CTSI will fund a total of thirteen new research projects through its Pilot and Collaborative Clinical and Translational Research Grants Program. This year’s investigative teams will conduct research on new therapeutic ways to treat anxiety in PTSD; look for better treatments for spinal cord injuries; search for answers to treating life-threatening intestinal disease affecting premature infants; the use of technology to better understand the brain of high-functioning children with autism; and many more.
These projects aim to create synergy through interdepartmental and inter-institutional collaboration and are specifically designed to lead to major future research support (i.e., PPG, SCORE, or large multi-PI interdisciplinary RO1 projects). The studies will explore the multidisciplinary and clinical potential of promising mechanistic findings that have the potential to be translated into improvements to clinical practice and community health.
The Pilot and Collaborative Clinical and Translational Research Grants Program advocates, facilitates and fosters the continuum of research from bench to bedside and from bedside to community practice. Support for the 2014 Pilot Award Program comes from Advancing a Healthier Wisconsin (AHW) and the National Institutes of Health (NIH).
Effects of Platelet Transfusions on Neonatal Hemostasis: An In Vitro Model
PI: Rachel Bercovitz, MD, Blood Center of Wisconsin
Co-Investigators: Debra Newman, PhD, Blood Center of Wisconsin; D. Woodrow Benson, MD, PhD Medical College of Wisconsin
Platelet transfusions treat and prevent bleeding in patients with qualitative or quantitative platelet defects. Thrombocytopenias associated with prematurity or iatrogenic platelet dysfunction are common indications for platelet transfusions in neonates. Neonates undergoing surgical repair of congenital heart defects are placed on cardiopulmonary bypass (CPB), which causes platelet dysfunction and subsequently increases risk of peri-operative bleeding. With no evidence-based guidelines from clinical trials, platelet transfusions are given empirically to prevent bleeding. This study utilizes an in vitro model of platelet transfusions where neonatal whole blood (transfusion “recipient”) and adult donor platelets are mixed to evaluate pre- and post-transfusion platelet function in neonates with quantitative or qualitative platelet disorders. This research will offer new insights into the change in hemostasis that results from platelet transfusions, and provide the necessary foundation for future clinical trials.
Novel Immunotherapy Delays the Onset of Type 1 Diabetes in NOD Mice
PI: Yi-Guang Chen, PhD, Medical College of Wisconsin
Co-Investigators: Katarina Midelfort, MS, PhD, Milwaukee School of Engineering; Michael Kron, MSc, PhD, Medical College of Wisconsin
Research needs for type I diabetes (T1D) include discovery of early biomarkers to identify individuals who will later develop diabetes, and new measures to delay, prevent or reverse the autoimmune loss of islet β-cell function. The “Hygiene Hypothesis” refers to the extensive scientific literature demonstrating beneficial properties of a controlled parasitic nematode infection on the course of animal and human autoimmune or inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, asthma and T1D. Our goal is to determine whether early immunization or prolonged treatment with recombinant Brugia malayi asparaginyl-tRNA synthetase (BmAsnRS) can delay the onset of T1D indefinitely. Therefore, this pilot proposal seeks to better define the power of BmAsnRS in preventing or delaying diabetes in the NOD mouse model by scaling up our study groups and evaluating cellular changes in vaccinated NOD mice with delayed diabetes. Ultimately we hope to apply these translational discoveries to the treatment or prevention of T1D in humans.
Photobiomodulation for the Treatment of Pressure Ulcers in Spinal Cord Injured Veterans
PI: Janis Eells. MS, PhD, University of Wisconsin—Milwaukee
Co-PIs: Vaishnavi Muqeet, Medical College of Wisconsin/VAMC; Hani Matloub, MD, VAMC
Co-Investigators: James Sanger, MD, VAMC; Joseph Berman, PT, VAMC
Photobiomodulation (PBM) by far-red to near-infrared light (630-900nm) modulates numerous cellular functions. For more than 40 years, PBM has been used in many parts of the world to increase the healing of chronic wounds. More recently, PBM using light-emitting diode (LED) arrays has been show to accelerate diabetic wound healing, prevent the development of chemo/radiation induced oral mucositis in pediatric bone marrow transplant patients and promote the healing of high intensity laser-induced retinal burns. An important objective of this study is a comprehensive characterization the mitochondrial metabolic state and the microenvironment of the chronic non-healing wound and the effect of 670 nm PBM on the metabolic state and microenvironment. To accomplish this objective, we will employ state-of-the-art mitochondrial redox imaging combined with measurement of concentrations and activity (by ELISA) of proinflammatory cytokines (TNFα and IL-6), tissue growth factors, (EGF and TGFβ), matrix metalloprotease (MMP9), and tissue metalloprotease inhibitor (TIMP1) in wound fluid and wound tissue biopsies. Oxidative stress will be assessed by measurements of nitrotyrosine and isoprostanes.
The Endocannabinoid System as a Therapeutic Target for Prevention of Post- Traumatic Stress Disorder
PI: Paul Gasser, BS, MS, PhD, Marquette University
Co-PI: Cecilia J Hillard, PhD, Medical College of Wisconsin
Co-Investigator: Linda K. Vaughn, Marquette University
Post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder precipitated by exposure to extreme emotional and/or physical stress. Approximately 7.7 million American adults are affected by PTSD in any given year, with a lifetime prevalence of 8.2%, greater than any other anxiety disorder. As corticosteroids interact with the endocannabinoid system (ECS), and the ECS plays an important role in the extinction of fear responses, these results raise the intriguing possibility that manipulations of corticosteroids and/or endocannabinoids may have therapeutic potential for PTSD patients. Our goal in this project is to advance the development of potential pharmacological tools for the treatment of PTSD by determining the role of the ECS in extinction of fear conditioning in vulnerable and resilient populations, and to examine the effects of manipulating endocannabinoids on fear responses in vulnerable and resilient populations.
Family Influences on Type 1 Diabetes Management in Young Children
PI: Astrida Kaugars, PhD, Marquette University
Co-PI: Amy Heffelfinger, PhD, MPE, Medical College of Wisconsin
Co-Investigator: Bethany Auble, MD, Medical College of Wisconsin
The rate of type 1 diabetes mellitus (T1DM) among young children is rising at an alarmingly fast pace. However, little is known about promoting effective T1DM management among young children despite their heightened vulnerability to poor health outcomes. It is crucial to employ a developmental perspective to understand the parent-child relationship within the context of T1DM management for young children. Moreover, it is essential to know the role of child, parent and family characteristics in influencing metabolic control and diabetes management in this age group. The current study will extend the use of a self-report measure of parents’ management of T1DM to an understudied population and identify the role of child, parent, and family characteristics in influencing the genesis of T1DM management among young children.
Multi-parametric Quantitative MRI of Spinal Cord Injury
PI: Tugan Muftuler, PhD, Medical College of Wisconsin
Co-Investigators: Shekar Kurpad, MD, Medical College of Wisconsin/ Zablocki VA Medical Center; Brian D. Schmit, PhD, Marquette University
Obtaining clinical measurements of the integrity of the spinal cord following traumatic injury remains a significant impediment to the planning of patient care. Although magnetic resonance imaging (MRI) is the state of the art approach for assessing the status of spinal cord tissue, there are still challenges to obtaining meaningful measures of spinal cord viability. Insults to the spinal cord result in structural and biochemical changes at and around the site of injury. Novel diagnostic imaging protocols could help the physician determine the viability of tissues and monitor pathologic changes that would impede recovery. Therefore, we propose to use a newly emerging technique called Diffusion Kurtosis Imaging (DKI) to study changes in tissue morphology after injury. While DKI would reveal changes in tissue morphology after SCI, it alone may not be sufficient for complete assessment of the injury. Complementary information about harmful biochemical changes might be needed to plan the best course of treatment. Therefore we propose a pilot study that employs DKI in combination with T1ρ MRI to investigate SCI lesions in a group of injured patients.
Heart Rate Variability and Apolipoprotein-E ε4 as Indices of Brain Activation and Cognitive Functioning in Middle Age and Older Adulthood
PI: Kristy Nielson, MA, PhD, Marquette University
Co-Investigators: Thomas Prieto, PhD, Medical College of Wisconsin; Anthony Porcelli, PhD, Marquette University; April Harkins, PhD, Marquette University; Thomas Chelimsky, MD, Medical College of Wisconsin
Alzheimer’s Disease (AD) costs an estimated $200 billion per year in the U.S.; its prevalence is expected to triple over the next 50 years. In order to better predict AD well before its onset, when interventions can be most effective, better and earlier biomarkers are greatly needed. Although AD neuropathology is thought to begin decades prior to diagnosis, little systematic study has occurred in middle age, when these changes are likely to begin and intervention or prevention might be most effective. Our recent studies using a semantic memory task have clearly shown functional MRI (fMRI) reveals aging-related cerebral hyperactivation, and hyperactivation in multiple AD-sensitive brain regions in healthy elders who carry the APOE ε4 allele, which are predictive of future cognitive decline. Age- and ε 4-related declines in ANS regulation may reflect a fundamental and modifiable mechanism underlying neural hyperactivation. As such, it may represent both an early index (i.e., biomarker) and a target for intervention. This pilot project will set the stage for a larger project focused on implementing and evaluating interventions.
Development of a New Diagnostic Assay for Heparin Induced Thrombocytopenia: A Comparative Effectiveness Study
PI: Anand Padmanabhan, MBBS, MA, PhD, Blood Center of Wisconsin/Medical College of Wisconsin
Co-Investigators: Namrata Peswani, MD, Medical College of Wisconsin; Richard Aster, and Janice McFarland, BloodCenter of Wisconsin/Medical College of Wisconsin; Daniel Bougie and Brian Curtis, BloodCenter of Wisconsin
Heparin induced thrombocytopenia and thrombosis (HIT) is a major cause of morbidity and mortality. It is a relatively common condition, affecting 1-5% of patients exposed to heparin. Thrombosis occurs in a significant subset of HIT patients and can be life-and-limb threatening. Accurate and timely diagnosis is a critical first step in the management of this serious condition. Our research efforts aim to develop a new, easy-to-perform, and accurate HIT assay that has the potential to be both highly sensitive and specific for the diagnosis of HIT. This comparative effectiveness study will evaluate diagnostic accuracy, sensitivity and specificity of the novel assay (based upon platelet p-selection expression) to that obtained with currently used HIT tests (ELISA and SRA) in a prospective consecutive series of samples received for testing. We also propose to study a well-characterized set of archived HIT samples on which clinical information and serology results are already available. Findings made are expected to help with enhancing diagnostic accuracy of this dangerous condition.
Reduced Neural Synchrony of Attention and Default-Mode Networks during Auditory Attention in Aging
PI: Merav Sabri, PhD, Medical College of Wisconsin
Co-Investigators: Colin Humphries, PhD, Medical College of Wisconsin; Ira Driscoll, PhD, University of Wisconsin—Milwaukee
The ability to attend selectively to specific sounds amidst irrelevant distractions is essential for daily cognitive function. Older adults demonstrate deficits in auditory attention, independent of hearing acuity. However, little is known about how the neural mechanisms of auditory selective attention change during aging. In our working model of auditory attention, we theorize that successful attention is the result of coupling between two large-scale neural systems. The focus of this proposal is to investigate changes in these two neural systems during healthy aging using behavioral measures and magnetic resonance imaging (MRI).
Immunogenetic Signatures of NEC
PI: Venkatesh Sampath, MD, MRCPCh, Medical College of Wisconsin
Co-Investigators: Pippa M. Simpson, PhD, Medical College of Wisconsin; David Dimmock, MD, Medical College of Wisconsin, John M Routes, MD, Medical College of Wisconsin, Demin Wang, PhD, Blood Center of Wisconsin
Necrotizing enterocolitis (NEC), a severe form of bowel disease that develops in 5-10% of premature infants, has a mortality of 25-40%. A deficiency in our understanding of host genomic factors that impact NEC pathogenesis has contributed to our inability to predict NEC or prevent it. Using a sequencing approach we have recently identified novel mutations in SIGIRR (Single IgG IL-1-Related Receptor); a gene that negatively regulates Toll-like receptor (TLR) and IL-1 receptor (IL-1R)-mediated inflammation in an infant who succumbed to NEC. Our preliminary data suggest that SIGIRR mutations abolish SIGIRR function and contribute to dysregulated TLR signaling in intestinal epithelial cells. The focus of this project is to establish SIGIRR as a locus for disease susceptibility in premature infants and to investigate the mechanisms by which SIGIRR variants modulate TLR-mediated inflammatory signaling in-vitro. Our broad long-term goals are to understand the immunogenetic signatures of NEC in premature infants and to develop immune strategies to decrease the burden of NEC.
Robotically-Enhanced Neuroimaging of Memory and Prediction in Children with Autism Spectrum Disorders – A Pilot Study
PI: Robert Scheidt, MS, PhD, Marquette University
Co-Investigators: Jinsung Wang, MS, PhD, University of Wisconsin—Milwaukee; Amy Vaughn Van Hecke, MS, PhD, Marquette University; Norah L Johnson, MSN, PhD, Marquette University; Sheikh Iqbal Ahamed, BSc, PhD, Marquette University
Sensorimotor dysfunction is a cardinal feature of autism spectrum disorders (ASD). However, little is known about how deficits in sensorimotor information processing relate to other behavioral deficits such as socio- linguistic learning impairments in children with ASD. The objective of this CTSI pilot project is to establish the tools, techniques and preliminary data needed to initiate a research program that will elucidate the causal relationship between deficits in neural processing of sensorimotor memories and predictions in ASD and socio- linguistic deficits. The knowledge gained will be instrumental in guiding development of therapies for reducing challenging behaviors in children with ASD by addressing underlying deficits of memory-based prediction. Our approach is to use functional magnetic resonance imaging, a simple video game and a novel robotic joystick to quantify how the brains of high-functioning children with autism and those of typically developing children process sensory information, encode that information into memories, and use those memories to shape future actions within a carefully-controlled but unpredictable physical environment.
The Effect of Breast Milk NADPH Oxidase Activity on Necrotizing Enterocolitis
PI: Scott Welak, MD, Medical College of Wisconsin
Co-Investigator: Lisa Brock, RN, Children’s Hospital of Wisconsin
Necrotizing Enterocolitis (NEC) is a life-threatening intestinal disease affecting premature infants. Its incidence approaches 10%, and the mortality may be as high as 30%. NEC contributes to morbidities in survivors, including intestinal failure, chronic lung disease and developmental delay. While the biologic mechanisms of NEC are incompletely understood, it is believed that NEC is a result of an abnormal inflammatory response by an incompletely development intestine. Expressed breast milk (EBM) is protective, but does not eliminate the risk of NEC. We hypothesize that small intestinal NOX activity increases in neonates fed milk with high levels of NOX and is associated with NEC in human infants. In order to test these hypotheses we will compare NOX activity in breast milk with the incidence of NEC. The study design allows correlation of cell culture, animal, and clinical outcomes from the same sample of milk.
The Effect of Moderate Intensity Physical Activity on Systemic and Local Microrna Expression in Older Adult Humans: Effects on Vascular Aging
PI: Michael Widlansky, MD, MPH, Medical College of Wisconsin
Co-Investigators: Alison J. Kriegel, PhD Medical College of Wisconsin; Mingyu Liang, PhD, Medical College of Wisconsin; Scott J. Strath, PhD, University of Wisconsin—Milwaukee
Our long term goal is to identify potential systemic modulators of the vascular aging process and determine their mechanisms of effect in the human vasculature. The goals of this application are to determine whether sustained increases in moderate intensity physical activity (PA) alter systemic expression of miRs related to shear stress, aging, and endothelial function and determine whether systemic miRs expression altered by moderate intensity physical activity mechanistically alter endothelial function in small human arteries. These investigations will provide key new information by identifying potential novel regulators of sedentary vascular aging for future translational studies.