The CTSI Pilot and Collaborative Clinical and Translational Research Grants Program has been designed to advocate, facilitate and foster the continuum of research from bench to bedside, and from bedside to community practice. Support for the Pilot Award Program comes from Advancing a Healthier Wisconsin (AHW), the National Institutes of Health (NIH), the Biotechnology and Bioengineering Center (BBC) and the John and Jeanne Byrnes CTSI Award. The Pilot Awards are intended to stimulate inter- and trans-disciplinary clinical and translational research among the CTSI partner institutions. These grants provide:
- Support to new and promising Clinical and Translational Projects
- A mechanism for junior investigators to focus efforts in Clinical and Translational Research
- A stimulus for collaborative research between bench and clinical investigators
- A mechanism for newly formed research teams that are formed at CTSI nucleating workshops which bring intellectual assets and research expertise together
A traineeship award was given this year to support the research projects of a CTSI translational tract graduate student to obtain preliminary data for use in applications to support multidisciplinary Clinical and Translational Research.
Two Novel Technology awards for the development of new and innovative technical resources were granted. The Novel Technology projects are funded through the John & Jeanne Byrnes CTSI Award which supports collaborative research in the life sciences requiring modeling, simulation and visualization techniques. These are projects seeking solutions to large-scale (systems-level) problems in coupling clinical and translational medicine; problems that typically require the use of high performance computing (HPC) systems and services.
A Novel Target for the Treatment of Schizophrenia
PI: M. Behnam Ghasemzadeh, PhD
Co-PIs: Dan Sem, PhD, Kambiz Pahlavan, MD and Joe McGraw
Schizophrenia is a devastating chronic mental disorder which disrupts personal, family, and social lives of affected individuals. The lack of new and effective medication for treatment of various symptoms of schizophrenia is reflected in the absence of discovery of significant cellular and molecular signaling mechanism(s) that can modulate the symptoms of the disease. We have identified the KCNQ potassium channel in the brain as a novel signaling mechanism that can be explored for treatment of schizophrenia symptoms. Inactivation of these channels leads to release of several neurotransmitters such as dopamine, glutamate, and acetylcholine in brain nuclei relevant to schizophrenia. The long term goal of this proposal is to develop KCNQ channel blockers as drug candidates for clinical testing.
Ex Vivo Thermoacoustic Imaging of Prostate Cancer
PI: Sarah Patch, PhD
Co-PIs: William See, MD, Kenneth Jacobson, MD and Holly Kelly, RN
Identifying sites of early cancerous involvement of the prostate gland has proven extremely challenging. In contrast to breast cancer, where mammography provides not only identification but also localization, there is no analogous imaging technology for prostate cancer. CT, MRI, MR spectroscopy, and multiple ultrasound techniques have poor sensitivity and poor specificity for disease detection [Trabulsi10]. Our study is designed to determine whether ex vivo TCT can detect ECE and if warranted, design a system suitable for a clinical trial of in vivo TCT prostate imaging.
Preclinical Study to Optimize Anti-tumor Immune Activation Against Neuroblastoma, Breast Cancer & Multiple Myeloma using a Cell-based Tumor Vaccination in Combination with Immune Modulating Agents
PI: Jill Gershan, PhD
Co-PIs: Byron Johnson, PhD, William Drobyski, MD, Carolyn Taylor, PhD, Meghen Browning, MD and Michael Bishop, MD
New approaches for the treatment of cancers that are refractory to conventional therapies are needed to prevent relapse and metastasis. Immunotherapy is a promising treatment adjuvant because anti-tumor immune effector cells are highly cell-specific and have the potential to indefinitely target micro-metastases for destruction via immune memory. Cancer vaccines have been developed to prime immune effector cells against tumor antigens; however, immune-regulatory pathways are in place that limit the activation of these cells against self or altered-self tumor antigens (a process referred to as immune tolerance). In response to this problem, many studies are currently focused on testing immune-modulatory therapies that not only activate innate and adaptive immune cells but also block immune inhibitory pathways to break immune tolerance. While anti-tumor immune therapies in animal models have provided evidence that tumor-specific cells can be activated to reduce or eliminate tumors, when translated to the clinic anti-tumor efficacy has typically been limited. The objective of this preclinical project is to optimize anti-tumor immune responses by combining various immune modulatory therapies, including tumor cell lysate vaccines and agents that activate the innate (CpG oligodeoxynucleotides, anti-CD40 agonist antibody) and adaptive (anti-CTLA-4 (CD152), anti-PD-L1, (B7-H1, CD274), anti-PD-1 (CD279) antibodies and lymphopenia with adoptive cell therapy (ACT)) arms of the immune response.
Changes in BMI and Intestinal Microbiota with Prebiotics, Probiotics and Synbiotics
PI: Marilyn Frenn, PhD
Co-PIs: Nita Salzman, MD, PhD and Pippa Simpson, PhD
More than 31% of the child population and 2/3 of the adult population is overweight or obese. This high incidence of obesity suggests not only genetic and environmental contributors (over nutrition and reduced physical activity), but also organisms normally found in the lower human intestine (gut microbiota) forming a “microbial organ” within human and animal hosts, which may increase or decrease obesity depending on the type of microbiota. The purpose of this research is to determine the feasibility, acceptability, and initial effectiveness of combining prebiotic and calcium treatment with a diet/physical activity educational program on body composition and intestinal microbiota among predominately overweight and obese 4th through 6th grade children. It is important to address overweight and obesity in childhood because 80% of children overweight at age 10 to 15 are obese at age 25. Obesity is most prevalent among those with low income, who do not finish high school, so intervening in schools reaches those most at risk.
Serum Endocannabinoid Concentration and Salivary Cortisol in Patients with Cyclic Vomiting Syndrome (CVS)
PI: Thangam Venkatesan, MD
Co-PIs: Cecilia Hillard, PhD and Hershel Raff, MD
Cyclic vomiting syndrome (CVS) is a chronic disorder that is characterized by stereotypic episodes of nausea and vomiting interspersed with symptom-free intervals. This disorder is associated with significant morbidity and has significant socioeconomic consequences. Data in humans have demonstrated a bidirectional interaction between stress and ECS; stress reduces endocannabinoid concentrations in the circulation and endocannabinoid concentrations are inversely related to the HPA axis response. The treatment of CVS is mostly empiric and consistently effective therapies are lacking. The purpose of this project is to pave the way for manipulating the endocannabinoid system and the HPA axis in developing new therapies for CVS.
Role of Tactile Sensation on Hand Motor Control and Functional Recovery After Stroke – an fMRI Study
PI: Na Jin Seo, PhD
Co-PIs: Guenaddy Tchekanov, MD, Wendy Huddleston, PhD, Michelle Johnson, PhD and Brian Schmidt, PhD
Stroke survivors exhibit impaired grip force control characterized by altered digit force direction due to excessive shear force relative to normal force at the digit-object interface. This altered digit force direction leads to a higher probability of finger-object slip, diminishing their ability to perform activities of daily living. Since grip control heavily relies on sensory feedback, not only motor deficit but also sensory deficit following stroke contribute to this altered digit force direction and grip impairment. Optimal sensory enhancement technique and brain’s response to enhanced sensation as it relates to plasticity are not well understood. This gap in knowledge imposes an obstacle in understanding brain mechanisms of repair and plasticity, which hinders advancement of effective assistive devices and therapeutic protocols for stroke survivors. Our long-term goal is to optimize stroke rehabilitation approaches via sensory manipulation to facilitate brain plasticity and motor recovery following stroke.
Bridging the Gap between Patient Perception of Quality and the Engineering Performance of Assistive Lower Limb Devices
PI: Joseph Schimmels, PhD
Co-PIs: David Del Toro, PhD, Stephen Guastello, PhD, Jessica Fritz, PhD and Philip Voglewede, PhD
Current methods used in the design of prosthetic and orthotic devices have inadequately considered the perceptions of the patient in establishing design performance criteria. This proposal addresses means of quantifying patient perception of prosthesis quality for use in the design process. A multidisciplinary team of engineers, clinicians, and psychologists will work together to better understand how patient perception of quality can be better formulated into engineering design criteria and likewise how product variation may affect a patient’s acceptance of a prosthesis. The scope of the work will be limited to trans-tibial (below the knee) prostheses.
Role of IgA and IgM Immunoglobulins in Heparin-induced Thrombocytopenia and Thrombosis (HIT)
PI: Anand Padmanabhan, MD
Co-PIs: Daniel Bougie, PhD, Brian Curtis, PhD, Janice McFarland, MD and Richard Aster, MD
HIT is a major cause of morbidity and mortality in patients receiving heparin and failure to diagnose this condition correctly can be catastrophic for affected patients. Therefore, timely and accurate diagnosis is critical. Antibodies specific for complexes of heparin and platelet factor 4 (PF4) are a hallmark of HIT but understanding of how these antibodies cause thrombocytopenia and how they trigger arterial and venous thrombosis is incomplete. Most HIT antibodies are of the IgG isotype, but IgA and IgM antibodies are common. Nonetheless, recent publications recommend that tests for HIT screening be structured to detect only IgG antibodies to improve diagnostic “specificity.” The BloodCenter of Wisconsin (BCW) performs HIT diagnostic testing on a large scale and has identified many patients suspected of having HIT who have IgA and/or IgM antibodies only, some of whom have had life-threatening thrombosis unexplained by any other cause. Anecdotal reports also implicate IgA/IgM antibodies as triggers for HIT. It is critical that the importance of IgA and IgM antibodies in HIT be defined before testing for antibodies of these isotypes is abandoned. The purpose of this project is to define the role of IgA and IgM antibodies in the pathogenesis of HIT and improve laboratory diagnosis and management of this condition. Studies described in Aims 2 and 3 may define new mechanisms by which HIT antibodies of any isotype can predispose patients receiving heparin to hypercoagulability and suggest new strategies for prevention and treatment of HIT-associated thrombosis.
The Role of SDF-1/CXCR4 Axis in Migration and Repair Capacity of Messenchymal Stem Cells Transplanted in In Vitro Model of Traumatic Brain Injury
PI: Aleksandra Glavaski-Joksimovic, PhD
Co-PIs: Milon Joksimovic, PhD
Traumatic brain injury (TBI) with its broad spectrum of symptoms and disabilities and associated high morbidity is a considerable health problem. There is no effective therapy for TBI, and current treatments are mainly focused on supportive measures and rehabilitation. There is increasing evidence that bone marrow-derived mesenchymal stem cells (BMSC) have potential to migrate toward the site of trauma and stimulate recovery of the damaged brain tissue after TBI. However, underlying mechanisms contributing to the BMSC migration and restoration of neurological functions are still largely unknown. In the proposed study, we aim to elucidate the role of stromal cell-derived factor 1 (SDF-1) and its cognate receptor chemokine receptor 4 (CXCR4) in the migration and rejuvenating effect of naive BMSC and bone marrow-derived neuroprogenitor-like cells transplanted in an in vitro model of TBI.
Mechanisms of Anti-microbial Effect of Blue Light on Methicillin Resistant Staphylococcus Aureus (MRSA)
PI: Violet Bumah, PhD
Co-PIs: Chukuka Enwemeka, PhD and Harry Whelan, MD
The overall goals of this study are: 1) To optimize the bactericidal effect of 470 nm light on MRSA, with or without hyperbaric oxygen (HBO), and 2) to determine its mechanism of action so as to foster the development of a therapeutic protocol for human cases of topical MRSA infections. Emerging evidence indicates that certain wavelengths of blue light kill MRSA, and there are studies which suggest that HBO suppresses the growth of MRSA.
Neural Mechanisms Underlying Functional Laterality of the Intact Arm of Upper-limb Amputees – An fMRI Study
PI: Jinsung Wang, PhD
Co-PI: Jeff Binder, MD
Upper-limb amputees’ employment and independent living depend heavily on the effective use of their intact limb. While many amputees use their intact limb for activities that were previously performed by the amputated limb, little is known regarding the efficiency of their intact arm use in performing those activities. A proper understanding of the intact arm’s functionality is critical not only for successful performance of activities of daily living with the intact limb, but also for prevention of re-injury associated with the intact arm use for certain vocational activities due to its inappropriate function. In the proposed study, we will examine human brain activity during targeted reaching movement performed by the intact arm of upper-limb amputees, using functional MRI, to determine whether functional laterality of the amputees’ intact arm will change after amputation.
Assessment and Prevention of Acute Kidney Injury Following Cardiopulmonary Bypass in Children Through Novel Application of Serum and Urine Biomarkers
PI: John Scott, MD
Co-PIs: David Hehir, MD, Aaron Dall, MD and Michael Mitchell, MD
Acute kidney injury (AKI) following repair of congenital heart disease with cardiopulmonary bypass (CPB) is common and carries unacceptable long-term morbidity and mortality. Through a multi-institutional and multi-disciplinary collaborative working group within the CTSI, we will evaluate the use of novel biomarkers of AKI in this population and integrate their use with continuous monitoring of regional oximetry through near infrared spectroscopy (NIRS). We hypothesize that the integration of NIRS, a continuous, highly sensitive monitor for changes in regional oxyhemoglobin saturation (rSO2) with highly specific biomarkers of AKI, which peak rapidly following injury, will allow clinicians to detect the development of AKI earlier and more effectively than current standard monitoring allows. In addition, we will investigate risk factors for the development of AKI, both by analysis of clinical variables and genetic predisposition. This work will increase our understanding of the determinants of post-CPB AKI, allowing for the development of goal directed therapies to prevent and treat AKI, ultimately translating into decreased morbidity and mortality.
Biomarkers in Diastolic Dysfunction/Heart Failure with Preserved Ejection Fraction
PI: Jennifer Strande, MD
Co-PI: Shama Mirza, PhD
Half of patients with heart failure (HF) have a preserved left ventricular ejection fraction (HFpEF). Morbidity and mortality are similar to values observed in patients with HF due to reduced EF, yet no effective treatment has been identified for HFpEF. Often the diagnosis of HFpEF is challenging and relies upon careful clinical evaluation, echocardiography with Doppler, and invasive hemodynamic assessment. There is a pressing medical need for minimally invasive objective metrics HFpEF in order to assist in the diagnosis, monitor therapy and intervene before irreversible cardiac damage is present. The focus of the work proposed in this grant application will be to elucidate the potential biomarkers that contribute to cardiac dysfunction in HFpEF.
Novel Cellular Immunotherapy for Treating High-risk Pediatric Solid Tumors
PI: Monika Thakar, MD
Co-PIs: S. Malarkannan, MD, Meghan Browning, MD and Kristina Schuldt, BS
Taking advantage of the therapeutic effects of GVT from both transplantation of allogeneic hematopoietic stem cells and the adoptive infusion of donor NK cells, we are conducting a Phase I/II study using this dual immunotherapy approach to treat high-risk solid tumors. We feel that our experience in performing human leukocyte antigen (HLA}-haploidentical transplantation with in vivo T cell depletion using post-transplant cyclophosphamide (CY)13 and our multi-institutional expertise in manufacturing clinical-grade NK cells under FDA-approved IND BB 13794, will allow us to successfully implement this clinical trial. Furthermore, our pilot data in three patients showing the safety of infusing donor NK cells in the post-transplant setting (preliminary data, Protocol 2230), provides strength and feasibility of this approach and allows us to expand this strate gy to treat high-risk relapsed or refractory pediatric and adult patients with solid tumors. Our study will also evaluate the relationship between different NK cell phenotypes and cytokines/chemokines that emerge from our cellular and adoptive immunotherapy approach and correlate our laboratory results to clinical outcomes. Finally, a validated quality of life survey will be administered to understand the consequences of our intervention on overall patient well-being. Such objective and descriptive endpoints will provide data to help guide future hypothesis-driven studies evaluating the relationship between NK cells and treatment response in this set of high-risk malignant solid tumors.
Parent-Child Interaction in a Motor and Communication Intervention for Toddlers with Down syndrome
PI: Victoria Moerchen, PhD
Co-PIs: Rachel Schiffman, PhD and Paula Ryner, PhD
This interdisciplinary project will use a parent-delivered treadmill intervention as the context within which to examine the contribution of the parent-child interaction to both the communicative and motor responsiveness of toddlers with Down syndrome. Our central hypothesis is that the parent-child interaction can be used to address the child’s development in activities targeting more than one developmental domain. Specific Aim 1: Determine the relationship between contingent behaviors of the parent to the child during the treadmill activity and the frequency of (a) toddler stepping and (b) toddler communicative behavior. Specific Aim 2: Test the feasibility of using an established standardized parent-child interaction tool to characterize dyadic interaction in the treadmill context. This study will develop a model of early intervention that optimizes the parent-child interaction as the primary mechanism for stimulating development of the child.
Image-guided Proteomics of Glioblastoma Multiforme – Moving Towards Personalized Medicine
PI: Shama Mirza, PhD
Co-PIs: Jennifer Connelly, MD and Kathleen Schmainda, MD
GBM is the most common primary malignant brain tumor. Surgery, radiotherapy and temozolomide improve survival and quality of life. Recurrence of GBM is commonplace, controlled temporarily with bevacizumab, an angiogenesis inhibitor that interferes with the formation of blood vessels that nourish GBM. The response of GBM to bevacizumab varies from patient-to-patient. The mechanisms involved in regulating individual tumor response or resistance to anti-angiogenic therapy is not understood. The knowledge of differential protein expression and mechanisms that mediate vessel formation and thereby tumor progression will reveal some of these mysteries. Identifying proteins responsible for angiogenesis in a given GBM could predict an individual’s response to therapy. The objective of this study is to characterize proteins mediating and regulating tumor angiogenesis in glioblastoma multiforme (GBM), and understand the mechanism involved in differential response to anti-angiogenic therapy using bevacizumab.
Computational Analysis of Transcranial Magnetic Stimulation
PI: Christopher Butson, PhD
Trainee: Brian Goodwin
Prior analyses in transcranial magnetic stimulation (TMS) have been performed to characterize the electromagnetic interactions between the magnetic field and the brain, but there are still many unanswered questions about the modulatory response of TMS. The long term goal of this research is to elucidate the mechanism(s) of TMS to improve its effectiveness as a neuromodulation therapy. The objective is to use multiscale, biophysically-based computational models to quantify of the degree, type, and location of neural modulation during TMS. The central hypothesis is that neural stimulation during TMS is dependent on the stimulation parameters (waveform type and amplitude) as well as position and orientation of the TMS coil relative to neural elements in cortex. The rationale behind this approach is that information from computational models can inform physiological studies of TMS, and potentially provide insights that would be difficult to obtain using either method alone. The approach is innovative because it uses biophysically-based computational models to make detailed predictions about the time-dependent effects of TMS on neural elements in cortex. The proposed research is significant because it could provide the information necessary to activate, or alternately avoid activating, cortical target regions using TMS.
Optogenetic-fMRI: A New Integrated Technology for Lab and Clinic
PI: Edgar DeYoe, PhD
Co-PIs: Ramin Pashaie, PhD and Christopher Pawela, PhD
The overall goal of this project is to design, assemble and test an integrated system for OBS-fMRI, demonstrate its use for exploring clinically relevant applications and then use the resulting technology and data as the basis for a subsequent proposal for federal funding. Optogenetics employs genetic manipulation of targeted brain cells to make them photoreactive thereby allowing them to be stimulated or inhibited repeatedly by appropriate laser light pulses delivered through implanted optical fibers. Functional MRI, on the other hand, has become the method of choice for in vivo neurophysiological analysis of brain function and, more recently, has been translated into a powerful clinical tool for diagnosis and treatment planning for patients with brain tumors and other focal pathologies. Functional MRI provides highly detailed maps of brain function in humans thus permitting the identification and targeting of key brain structures involved in specific sensory, motor or cognitive functions. Together, fMRI and optogenetics become complementary; the first allows us to “read” brain activity and the second allows us to manipulate brain activity. In addition, OBS itself can evoke fMRI responses in brain regions to which the optically stimulated cells project thereby identifying functionally causal relationships between brain sites. Though the potential applications of this combined technology are very broad, the focus of the proposed pilot project is to develop and explore its use in clinically motivated applications. To accomplish this, an interdisciplinary team from UWM Electrical Engineering, and MCW’s Radiology and Plastic Surgery departments will be assembled in order to capitalize on unique local strengths in both optogenetics and MR imaging.
Treating Patients’ “Real” Avatars in Virtual Medical Offices
PI: Fatemah Zahedi, PhD
Co-PIs: Hemant Jain, PhD, Nitin Walia, PhD and Reza Shaker, MD
With rising cost of healthcare and increasing demands for healthcare in a graying population, drastic changes are in urgent need to deal with the healthcare crisis. This project provides an alternative approach to the delivery of medical care that accomplishes two seemingly conflicting objectives simultaneously: substantially lowering cost while improving accessibility. The approach we propose is to deliver healthcare in three-dimensional (3D) virtual worlds through interactions of patients’ “real” avatars and physicians’ avatars. We define “real” avatars as those that embody patients’ physiological data in real time. The goal of this proposal is to build a remote-sensing system that captures patients’ physiological data and embeds the data into patients’ avatars. Virtual medical offices require only a small fraction of the cost of building and maintaining bricks-and-mortar medical offices, make medical services available regardless of patients and physicians geographical locations, and could operate 24/7 from any place in a region, country, or even around the globe. Thus, it accomplishes two goals simultaneously: substantially decreasing the cost of medical services and increasing accessibility to medical care.
The CTSI Pilot and Collaborative Clinical and Translational Research Grants Program has been designed to advocate, facilitate and foster the continuum of research from bench to bedside, and from bedside to community practice. Support for the Pilot Award Program comes from Advancing a Healthier Wisconsin (AHW), the National Institutes of Health (NIH), the Biotechnology and Bioengineering Center (BBC) and the John and Jeanne Byrnes CTSI Award.