Translational Basic & Clinical Pilot Awards ($50,000 for 12 Months)

2017 Pilot Awards Program

Translational Basic & Clinical Pilot Awards ($50,000 for 12 months)

Creating Epigenetic Switches for Triplet Repeats of Fragile X Syndrome

PI: Aseem Ansari, PhD, College of Agriculture & Life Sciences

Collaborator: Xinyu Zhao, SMPH

Summary: Fragile X Syndrome is caused by mutation in the FMR1 gene, which leads to a developmental delay, cognitive impairment and autism. The mutation, often a CGG triplet repeat, expands up to 200 times to cause a "pre-mutation" state; expansions more than 200 times lead to methylation of the transcribed 5' UTR regions resulting in gene silencing. We will use the requested funds to synthesize a focused library of sequence-specific gene targeting small molecules against the CGG repeats and test their ability to stimulate the expression of FMR1 in a cell-based reporter screen.

Robo Signaling Controls the Organization of the Islets of Langerhans

PIs: Barak Blum, PhD, Matthew Merrins, PhD, School of Medicine & Public Health

Co-Funding: UW Stem Cell and Regenerative Medicine Center

Summary: Pancreatic islets of Langerhans display precise spatial organization of their various endocrine cells that is essential for functionally accurate insulin secretion. Although the process of islet organization during development is well documented, the mechanisms controlling it remain obscure. This project will have direct translational impact on regenerative biology and tissue engineering approaches to produce islet-like micro-organs from pluripotent stem cells to be transplanted into Type-1 diabetics, as well as preserving islet architecture in Type-2 diabetics. In the next step, we will use the lessons learned in this award to use Robo signaling to derive functionally mature islet-like mini organs from human pluripotent stem cells.

Identifying Inflammatory Bowel Disease (IBD) Patients with Altered Immunity at Risk for Herpes Zoster

PIs: Freddy Caldera, DO, School of Medicine & Public Health; Mary Hayney, PharmD, MPH, School of Pharmacy

Collaborators: Arnold Wald, Sumona Saha, SMPH

Summary: IBD is a group of chronic inflammatory disorders of the gastrointestinal tract. Immunosuppressive therapy is the cornerstone of treatment for IBD, which while effective, increases the risk for infections, including Herpes zoster (HZ). HZ is caused by reactivation of varicella zoster virus (VZV) which can occur when T cell function declines. HZ is preventable with immunization. We postulate that IBD patients have altered cell-mediated immunity, which increases their risk for HZ. We will determine whether having IBD alters VZV cell-mediated immunity (CMI), which could lead to increased risk of HZ in this population. If our IBD cohort has lower or equivalent CMI, we would suggest universal HZ immunization for all IBD patients older than 40 years.

Developing a Human Pluripotent Stem Cell-Derived 3D Vascularized Cerebral Organoid Culture System

PI: William Daly, PhD, School of Medicine & Public Health

Collaborators: William Murphy, COE; Qiang Chang, SMPH

Co-Funding: UW Stem Cell and Regenerative Medicine Center

Summary: Recent advances in generating cerebral organoids that self-organize into neuralized structures demonstrate promise as tools for understanding and developing new therapies for neurodevelopmental disorders. Still, several major challenges remain. Specifically, even the best organoid culture system available now can only recapitulate rudimentary cortical features of very early stages of cortical formation with low reproducibility. We expect the incorporation of vasculature into the cerebral organoids will allow the organoids to mimic the later stages of brain development beyond what is currently possible. Once established, the model system will be utilized to model neurodevelopmental disorders; to assess drug efficacy in the disease models; and to screen for potential developmental neurotoxins.

Motion-robust quantitative MRI of the abdomen

PIs: Diego Hernando, PhD; Kevin Johnson PhD, School of Medicine & Public Health

Collaborators: Scott Reeder, Jennifer Rehm, SMPH

Co-Funding: UW Department of Radiology

Summary: An estimated 15% of children in the US are overweight or obese, with excess fat deposition in subcutaneous and ectopic (eg: liver) compartments. Liver fat can be assessed non-invasively using chemical shift-encoded magnetic resonance imaging (CSE-MRI) techniques. Nonetheless, current CSE-MRI methods require a 20-second breath-hold to avoid severe motion artifacts. Unfortunately, ~40% of children are unable to sustain such prolonged breath-holds. In this proposal, we will develop, optimize and validate a technique for accurate, precise and reproducible liver fat quantification in pediatrics. Development of motion-corrected averaging may open the door to a broad range of motion-robust quantitative MRI applications, including fat quantification in other organs (eg: pancreas), as well as relaxometry and diffusion MRI of the abdomen.

Assessment of Early vs. Delayed Catheter Intervention for Management of Pulmonary Artery Stenosis

PI: Luke Lamers, MD, School of Medicine & Public Health

Collaborators: Christopher Francois, SMPH; Punam Saha, University of Iowa

Summary: In the field of congenital heart disease (CHD) care in infants and children, there exists a critical need to better understand the effects of interventions for pulmonary artery (PA) stenosis. While survival following CHD surgery has risen dramatically, significant long-term issues remain. Completion of this study will, for the first time, generate detailed data providing guidance to clinicians encountering this common clinical problem and inform better decisions about timing of intervention to promote optimal long-term health.

Targeted Treatment for Pulmonary Hypertension Associated with Congenital Diaphragmatic Hernia

PIs: David McCulley, MD, School of Medicine & Public Health; Shaoqin Gong, PhD, College of Engineering

Collaborator: Naomi Chesler, COE

Summary: Congenital diaphragmatic hernia (CDH) is among the most common structural birth defects. Infants with CDH often do not survive after birth due to abnormal development of the lungs and pulmonary vasculature causing lethal pulmonary hypoplasia and pulmonary hypertension. With a foundation of direct patient care experience and improved understanding of the genetic and molecular basis of pulmonary hypertension, we plan to develop and test a novel drug targeting approach using a murine model. Our central hypothesis is that microparticle-targeted delivery of agents, such as Y-27632, to the dysfunctional pulmonary vascular smooth cells, will improve their therapeutic benefit and reduce pulmonary hypertension, while minimizing systemic side effects.

PIs: Sivan V Meethal, PhD; Bermans Iskandar, MD, School Medicine & Public Health

Summary: Experimental interventions aimed at improving injured adult central nervous system (CNS) recovery remain disappointing partly because the adult CNS has poor regenerative capacity. Our laboratory has previously shown that folic acid (FA), a dietary supplement and the key methyl donor in the mammalian CNS, can promote axon regeneration and recovery after spinal cord injury in-part via DNA methylation. We hypothesize and show preliminary results that indicate that the group of demethylating enzymes called Ten eleven translocases (TETs) play a key role in increased DNA demethylation at higher doses of FA, in turn leading to decreased axon regeneration after CNS injury. We propose 1) to examine the expression, activity and role of all the three TET enzymes (TET1, TET2, TET3) in axon regeneration after spinal cord injury in a pig model at escalating doses of folic acid (Aim1); and 2) to determine the effectiveness of non-toxic inhibitors of TET in enhancing axon re-growth with and without FA (Aim 2). Successful completion of these experiments will characterize the role of TET enzymes in epigenetic modulation of CNS regeneration and its relationship to FA treatment, and potentially lead to the identification of a combinatorial therapy (e.g., FA and TET inhibitor) that enhance CNS repair.

Investigation of a Novel Role for HAPLN1 in Multiple Myeloma Drug Resistance

PIs: Shigeki Miyamoto, PhD; Natalie Callander, PhD, School Medicine & Public Health

Co-Funding: UW Carbone Cancer Center

Summary: Multiple myeloma (MM) generally affects older people (median age at diagnosis 69), represents ~18% of hematologic malignancies and is currently incurable with a 48.5% 5-year survival. Although newer drugs, such as the proteasome inhibitors (e.g., bortezomib) and the immunomodulatory drugs (IMiDs) (e.g., lenalidomide) enable better clinical responses, development of drug resistance is still a major cause of death. Thus, identification of critical resistance mechanisms could lead to the development of new therapeutics for this disease. Upon accomplishment of the study, we will pursue HAPLN1 as a new therapeutic target (e.g., development of neutralizing antibody and/or chemical inhibitor) and a new biomarker for combatting the major problem of MM drug resistance.

Novel Methods Pilot Grant Awards ($50,000 for 12 months)

Novel Robotic Cycle Therapy for Targeted Neural Plasticity

PI: Peter Adamczyk, PhD, College of Engineering

Collaborators: Vivek Prabhakaran, Veena Nair, SMPH

Summary: The proposed project is a pilot investigation of novel methods for lower limb neuromotor rehabilitation following neurological injury such as stroke, applied through a novel robotic rehabilitation bicycle. The proposed cycle-based approach provides programmable rewards and penalties to incentivize motor recovery through neuroplasticity in the motor cortex. Specifically, this is the initial comparative efficacy study in patients to determine whether the proposed form of robotic cycle therapy is superior to current state-of-the-art cycling therapy. We will perform a 1-month, 12-session therapy protocol with matched and dosage-controlled Experimental and Control groups (n=12 each). We expect greater improvements in performance and brain activity in the Experimental group.

Advanced Quantitative Tissue Characterization with Confounder-Corrected MRI

PI: Scott Reeder, MD, PhD, School of Medicine & Public Health

Collaborators: Diego Hernando, Adnan Said, Rashmi Agni, Rao Watson, SMPH

Summary: The overall goal of this proposal is to develop a novel magnetic resonance imaging (MRI) method for quantitative characterization of fat- and iron-containing tissues. During the past decade, emerging “quantitative imaging biomarkers” have been developed for detection and quantification of multiple diseases in a variety of organs. In this project, we propose the development of a novel MRI method that simultaneously estimates quantitative biomarkers of tissue fibrosis (T1), tissue iron content (R2*) and fat concentration (proton density fat fraction (PDFF)). If successful, we anticipate broad applicability of this novel method for early detection and quantification of tissue fibrosis, iron and fat, in a wide variety of diseases and organs. To achieve the goals set forth in this application we have assembled an interdisciplinary team of both established and new collaborators that includes radiologists, electrical engineers, physicists, hepatologists and pathologists.

Optical Scattering as a Novel Biomarker for Glaucoma Susceptibility

PIs: Jeremy Rogers, PhD, College of Engineering; Gillian McLellan, DVM, School of Medicine & Public Health

Summary: Glaucoma is a leading cause of irreversible blindness, with a global prevalence that is increasing as the population ages. The goal of this project is to build a novel light scattering instrument and use it to develop a biomarker of glaucoma susceptibility by characterizing micro- and nano-structural alterations in the sclera. The low cost, fast, non-invasive optical scattering contrast techniques developed through these proposed efforts will be poised for clinical translation. Application of optical scattering techniques as a screening tool in a clinical setting will help to identify patients at greatest risk of glaucoma and disease progression, enhance ongoing genomic studies by providing critical information on ECM properties, and advance the application of precision medicine in glaucoma management.

A New Model for Studying Cell Trafficking and Proliferation in vivo

PI: Matyas Sandor, PhD, School of Medicine & Public Health

Collaborator: Sarah Marcus, SMPH

Summary: We propose to develop and test a new Cre-activated, photoconvertible Kikume Green-Red fluorescent transgenic mouse, allowing for cell line or molecule specific expression of this photoconvertible protein by crossing with specific promoter driven Cre-recombinase expressing mice, of which a large library is commercially available. In these mice, a selected cell type will fluoresce green, but upon illumination with violet light, they convert to red in a region localized to the light exposure. The movement of red cells to other sites, and of green cells into red, photoconverted areas can be followed by in vivo imaging, immunofluorescent microscopy, or flow cytometry. This new tool would improve cell-specific localized imaging for following cell fate, cell trafficking in physiological and disease conditions, and help models of inflammation, autoimmunity, cancer, and infectious disease analyze cells in a new way.

UW Emergency Department Research Services Program

PIs: Manish Shah, MD, MPH; Brian Patterson, MD, MPH, School of Medicine & Public Health

Collaborators: Azita Hamedani, Michael Pulia, Michael Repplinger, SMPH

Summary: Researchers have recognized the challenges surrounding performing research in busy and time sensitive clinical environments such as the Emergency Department (ED). The overall goal of this proposal is to create an UW-Emergency Department Research Services Program that employs cutting edge methodologies to identify and enroll eligible ED patients and visitors into research studies and complete research protocols for those studies. This core institutional resource will advance the research mission of the Department of Emergency Medicine and to support acute care researchers throughout the institution. By successfully establishing this Program and piloting new informatics methods for recruitment, we will support the broader institutional need to develop a more efficient clinical and translational research enterprise.

ICTR Co-Funding of 2017 UW Alzheimer’s Disease Research Center Pilots

A Non-Invasive Method for Assessment of Estradiol in the Brain

PI: Ei Terasawa-Grilley, PhD, School of Medicine & Public Health

Collaborators: Onofre DeJesus, SMPH; School of Medicine & Public Health Waisman Center

Summary: In the proposed project, we will first establish and validate a standard method for synthesizing 11C-centrozole from the precursor. Second, we will examine if the distribution pattern and 11C-centrozole uptake intensity in an ovariectomized aged monkey differs from those in an ovariectomized young monkey. Finally, we will determine if estradiol treatment changes aromatase synthesis in the brain of the same monkeys. Visualization of aromatase expression as an indicator for neuroestradiol synthesis by brain imaging facilitates defining the role of neuroestradiol in Alzheimer’s Disease. Additionally, the establishment of a non-invasive method for monitoring estradiol synthesis will add a resource for the campus as a research tool as well as a diagnostic tool.

Association of Cardiovascular Risk Factors with Micro- and Macrovascular Cerebral Function in Whites and African Americans

PIs: Heather Johnson, MD; Lindsay Clark, PhD, School of Medicine & Public Health

Summary: This project will utilize existing infrastructure and data from the Wisconsin Alzheimer’s Disease Research Center’s Clinical, Neuroimaging, and Minority Recruitment cores. Our interdisciplinary collaboration will use novel cerebral imaging techniques (arterial spin labeling, 4D-flow MRI) to evaluate relationships between cardiovascular disease risk factors, Alzheimer’s Disease cerebrospinal fluid biomarkers, and genetic risk factors to micro- and macrovascular cerebral blood flow among a diverse population.

ICTR Co-Funding of 2017 UW Skin Disease Research Center Pilots

Development of a Novel Synthetic Model to Study Skin Polarity

PI: Hao Chang, PhD, School of Medicine & Public Health

Summary: The overall goal of this application is to develop an in vitro synthetic model of planar cell polarity (PCP) and use this model to dissect the mechanisms that regulate skin polarity. PCP has been found to control multiple developmental processes, including hair follicle patterning, neural tube closure, palate closure, inner ear sensory hair cell patterning, kidney and lung development. Mutations in PCP genes have been linked to a variety of human diseases and/or developmental defects in experimental animals. These experiments will broaden our understanding of the mammalian PCP pathway and facilitate the development of therapeutic interventions for PCP-related diseases, such as neural tube closure defects, deafness, polycystic kidney disease, axon guidance defects, cleft palate and congenital heart disease.

Dietary Grape in the Management of Atopic Dermatitis

PI: Chandra Singh, PhD, School of Medicine & Public Health

Collaborators: Nihal Ahmad, Stefan Schieke, SMPH

Summary: The goal of this study is to determine the efficacy of dietary grape against atopic dermatitis (AD) in NC/NgaTnd mice, which express spontaneous AD most precisely. AD is common and in its severe form is devastating. Recently, several of the grape antioxidants have shown to be beneficial against dermatological conditions including AD. The outcome of our proposed study will define the beneficial effect of grape powder against AD, and molecular mechanism(s) of the biological effects of grape powder. Overall, this project will be the ideal translational opportunity in designing novel strategies for the management of AD.

COMMUNITY ENGAGEMENT AND RESEARCH

Clinical & Community Outcomes Research Pilot Awards ($75,000 for 12 months)

Instrument Development for a Social Network Analysis (SNA) of Antibiotic Prescribing in Skilled Nursing Facilities

PI: Christopher Crinch, MD, School of Medicine & Public Health

Academic Collaborators: Marlon Mundt, Paula Lueras, SMPH

UW Program Partners: UW Survey Center, Wisconsin Network for Research Support

Community Collaborators: Badger Prairie Health Care Center, Leading Age, Wisconsin Health Care Association, Wisconsin Medical Directors Association

Summary: Antibiotics are a common cause of adverse drug events, antibiotic resistance and Clostridium difficile infection (CDI). Older adults, such as those residing in a Skilled Nursing Facility (SNF), are more susceptible to the adverse consequences of antibiotics, which underscores the importance of appropriate antibiotic use in this population. The relationship between nursing home staff and PCP is an important one to understand if we want to improve antibiotic prescribing. Although the decision to prescribe an antibiotic is the responsibility of the prescriber, many individuals at the SNF interact with the prescriber to provide important clinical information used to make the antibiotic decision. Social Network Analysis is a promising method to understand the antibiotic decision-making process in SNFs. In this study, we propose development and validation of a data collection instrument for conducting a SNA of the SNF antibiotic prescribing network. Our goal is to investigate how the interactions between the nursing home staff and PCPs influence the decision to prescribe an antibiotic. By studying the interactions between nursing home staff and PCPs, we hope to improve how healthcare professionals work together as a team to deliver the best care possible to older adults.