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Collaborative Research Grants (IUCRG) — 2012-13 Recipients

Role of the Epigenetic Regulator Cfp1 in hematopoietic stem cell (HSC) response to stress; Nadia Carlesso and Yunlong Liu (School of Medicine), David Skalnik (School of Science, IUPUI)

Sepsis is a clinical syndrome, a devastating consequence of bacterial infection that is currently the primary cause of death in non-coronary intensive care units. In the United States, 750,000 people annually develop sepsis as a consequence of overwhelming bacterial infections and more than 200,000 of them die. Groups that are at particular risk for sepsis are patients with cancer, diabetes, chronic heart disease, and premature neonates. Thus, it is of foremost importance to find novel approaches to guide our understanding and treatment of severe bacterial infections. While most studies have focused on the late consequences of sepsis, little is known about the changes occurring in the bone marrow (BM) at early stages of blood cell formation and differentiation during acute inflammatory stress, and how these changes negatively affect the hematopoietic response to bacterial infection. Our preliminary data led us to hypothesize that the inflammatory stress triggered by bacterial infection induces permanent changes in the differentiation program of BM hematopoietic stem cells, inhibiting their ability to generate differentiated cells and to mount an efficient immune response against the pathogens. To test this hypothesis, this research will involve three groups of researchers—Nadia Carlesso (stem cells), David Skalnik (gene regulation), and Yiunlong Liu (bioinformatics)—working together to provide proof of the principle that CFP1 and similar DNA regulators are involved in sepsis response. The long-term goal of this interdisciplinary project is to identify specific molecules that can be targeted to prevent the devastating consequences of sepsis.

Mechanism of the non-classical release of EMAPII; Matthias Clauss (School of Medicine), David Clemmer (College of Arts and Sciences, IU Bloomington), Horia Petrache and Fangqiang Zhu (School of Science, IUPUI)

The building blocks of human tissue are cells, which are embraced by a protective membrane to keep cellular proteins inside. These cells secrete proteins, which travel in body fluent including blood to communicate with other cells and can be distinguished from non-secreted cell protein by the fact that they contain sugar molecules attached to their protein backbone, i.e. they are glycosylated. However, there is a third class of proteins, which is non-glycosylated, contained in cells under physiological conditions, but released upon stress. So far researcher have identified such proteins to be involved in wound repair and acting as cell growth stimulating molecules. We have recently identified such a protein, called EMAPII, which is normally kept in cells, but released upon stress such as cigarette smoke to causes tissue destruction by killing specific cells of blood vessels. Unfortunately, cigarette smoke causes a rapid and massive release of EMAPII, and when cigarette smoke is inhaled for long time tissue destruction is caused at lung sites, where oxygen is supposed to be taken up from the blood stream, leading to pulmonary emphysema. We propose to analyze mechanisms of the non-classical release of EMAPII from cells in response to cigarette smoke. We will employ molecular and biophysical methods, supported by computer modeling, to provide new insights into mechanisms for proteins to cross membrane. This may help identifying new targets to stop release of EMAPII, which is believed to play a major role in lung emphysema.

Genetic link of peptidoglycan recognition proteins with inflammatory bowel disease Dipika Gupta (School of Medicine, IU Northwest), Iztok Hozo (College of Arts & Sciences, IU Northwest)

Patients with inflammatory bowel disease (IBD), which includes Crohn’s Disease (CD) and ulcerative colitis (UC), suffer from chronic inflammation, abdominal pain, diarrhea and often malnutrition. The precise cause for the IBD pathology remains unknown. Peptidoglycan recognition proteins (PGLYRPs) are innate immunity antibacterial proteins that promote maintenance of beneficial microbial flora in the intestine, which protects mice against experimental colitis. The overall hypothesis of our current project is that human PGLYRPs protect against colitis by maintaining beneficial gut flora, and that changes in the expression or function of any of the four PGLYRP genes contributes to the pathogenesis of IBD in humans. This project will test the hypothesis that genetic polymorphisms in PGLYRP1, PGLYRP2, PGLYRP3 and PGLYRP4 genes associate with IBD in humans. Polymorphisms in PGLYRP genes will be identified in DNA samples from CD and UC patients, population controls, and CD and UC familial controls and analyzed using tests of association to identify variants that are significantly different between patients and controls. Variants that associate with CD and/or UC will be analyzed for their effect on expression and/or function of PGLYRPs. Thus, this project will identify the genetic association between PGLYRPs and IBD, provide predictability markers for sensitivity to intestinal inflammation, and identify nucleotide variants that may contribute to altered expression and/or function of these antibacterial proteins. These results will increase our understanding of the molecular mechanisms that contribute to the pathogenesis of IBD, which will facilitate the development of new prevention and treatment strategies for intestinal inflammation.

A Longitudinal Analysis of Project Lead the Way in Indiana; Robert Helfenbein (School of Education, IUPUI), Shanna Stuckey and John Houser (Center for Urban and Multicultural Education, IUPUI), Charles Feldhaus (School of Engineering & Technology)

According to the United States President’s Council of Advisors on Science and Technology, economic forecasts indicate the United States will need one million more college graduates in STEM fields over the next decade than are expected under current conditions. To reach this goal, the Council recommended an educational transformation in the US by strengthening K-12 students’ foundations in STEM subjects, motivating students to study STEM and consider STEM careers, and increasing retention in STEM majors at the post-secondary level. Project Lead the Way (PLTW) is a provider of STEM education curricular programming in secondary schools across the United States whose mission and model is largely consistent with the above three action plans, and that has had a presence in over 300 schools in Indiana. This study aims to assess the impact of PLTW by tracking high school and college level outcomes for those who participated in PLTW relative to similar peers. By linking data from high school graduates across Indiana with records from universities nationwide, researchers from the Center for Urban and Multicultural Education in the IUPUI School of Education (CUME) and IUPUI STEM Education Research Institute (SERI) hope to identify how PLTW impacts high school and college level outcomes for its participants, as well as determine if outcomes differ by student and school demographics.

Novel analgesic mechanisms for suppressing excessive glutamate signaling through targeted disruption of protein-protein interactions; Andrea G. Hohmann and Yvonne Y. Lai (College of Arts and Sciences, IU Bloomington), Andy Hudmon (School of Medicine)

Excessive signaling by glutamate, the major excitatory neurotransmitter in the brain, plays a causal role in the development of chronic pain and other pathological disorders of the nervous system. Activation of NMDA receptors by glutamate triggers a signaling cascade inside the cell that requires the enzyme neuronal nitric oxide synthase. However, NMDA receptor antagonists have limited therapeutic potential as analgesics because blockade of NMDA receptors is associated with adverse side-effects which constrain therapeutic dosing. Our long-range goal is to identify mechanisms for suppressing pathological pain that lack unwanted side effects. The objective of the present application is to validate small molecule disruptors of a key signaling pathway underlying aberrant neuronal excitability as analgesics. We propose to disrupt the specific interaction between two proteins required for the nitric oxide signaling cascade downstream of NMDA receptor activation. Targeting this pathway would be expected to suppress excitoxicity and pathological pain without the adverse side-effects associated with direct antagonism of the NMDA receptor itself. Completion of the proposed work will: i) broadly validate the approach of using protein-protein interaction inhibitors as drugs; ii) increase our understanding of the dynamics of neuronal signaling complexes implicated in pathological states; and iii) support development of potential clinical candidates for drug development.

A Novel Multimodal Methodology to Investigate Communicative Interactions between Parents and Deaf Infants Before and After Cochlear Implantation; Derek Houston (School of Medicine), David Crandall (School of Informatics and Computing), Tonya Bergeson-Dana (School of Medicine), Linda Smith, David Pisoni, Chen Yu (College of Arts and Sciences, IU Bloomington)

Cochlear implants (CIs) are biomedical devices that give deaf infants and children the opportunity to hear and learn spoken language. However, sound through a CI is not nearly as rich as sound through a healthy ear, and many children who receive CIs lag behind their normal-hearing peers in language development. To understand how deaf infants’ early communication skills develop following cochlear implantation, this project joins researchers in the DeVault Otologic Research Laboratory in the IU School of Medicine with developmental, cognitive, and computer scientists at IU-Bloomington to implement a new methodology (developed by our Bloomington members) that uses head-mounted cameras and eye trackers to obtain high-density data on parent-infant communicative interactions. Most studies on infant language development use highly constrained procedures that allow control over extraneous factors at the expense of the richness of information that comes from natural interactions. Our methodology uses sophisticated methods of integrating, analyzing, and data mining parent-infant interactions that allows us to perform micro-level behavioral analyses of events such as the rate at which infants and parents both look at an object when the parent names it. We also analyze how these events translate into word learning in subsequent testing. With clinical populations, individual differences in language development are clinically meaningful and need to be understood so that therapy can be individually tailored. By having the ability to data-mine information-rich communicative interactions, this study has the potential to lead to a better understanding of best practices for enhancing language development of this important clinical population.

Thrombopoietic Agents in Bone Regeneration: Development of a Minipig Bone Healing Model; Melissa Kacena, Michael S. Sturek, and Christine Boehm (School of Medicine), Tien-Min Gabriel Chu (School of Dentistry)

Reconstruction of large bone defects resulting from bone tumors, sports injuries, trauma such as that caused by car accidents, gunshot wounds or high-energy blast injuries seen in military conflicts, has long been a challenge for orthopaedic surgeons. Failure to heal these bone injuries may result in multiple returns to the operating room, significant pain and problems, increased risk of infection and complications, and loss of leg or arm function or even amputation. Therefore, finding new ways to treat bone healing problems is important. We found that thrombopoietic drugs, drugs known to increase platelet (clot blood) numbers, can enhance bone healing in mice and rats. The long-term goal of this research is to determine whether our mouse and rat bone healing data applies to humans. An important first step is to prove this can work in larger animals which are more similar to humans, and here we will examine bone healing in minipigs. Drs. Melissa Kacena (School of Medicine) and Tien-Min Gabriel Chu (School of Dentistry) began a highly productive collaboration demonstrating that thrombopoietic drugs may serve as new bone healing drugs. Here we will form a new collaboration with Drs. Michael Sturek and Chris Boehm (both School of Medicine) to develop a minipig bone healing model and to begin testing the ability of thrombopoietic drugs to heal bones in large animals which are more representative of human bone healing.

Translational Biomarkers in a Rodent Model of Schizophrenia; Christopher Lapish (School of Science), Brian O’Donnell and Dae Jin Kim (College of Arts and Sciences, IU Bloomington), Alan Breier and Jennifer Vohs (School of Medicine)

A major barrier in the investigation of the underlying cellular mechanisms in schizophrenia and the development of novel treatments is the lack of validated biomarkers for the disorder that can be applied across species. This project will employ state of the art measures of neural synchrony that are commonly altered in individuals with schizophrenia, and test them in rodent models that express schizophrenia-related phenotypes. These studies will employ an increasingly popular “two-hit model” of schizophrenia to probe changes in brain function exhibited by these animals, and by extension, in schizophrenic individuals. The immediate goals of this proposal are to first, assess neurophysiological biomarkers observed in schizophrenia in the aforementioned rodent model. Second, we will test whether a compound that is currently being assessed as a novel treatment for schizophrenia, N-Acetyl Cysteine, reverses these deficits in the rodent model of schizophrenia. The project forms an interdisciplinary team of preclinical and clinical researchers across IUPUI, IUB, and the IUSOM to meet these goals. The experiments in this proposal will improve our understanding of the specific changes in brain function that underlie schizophrenia, and develop novel diagnostic tools to assess potential treatment strategies.

Real-time processing and visualization for cellular-resolution ophthalmoscopy; Donald Miller (School of Optometry), Jaehwan John Lee (School of Engineering and Technology)

Diseases of the eye, including those that cause permanent blindness, fundamentally begin at the cellular and molecular levels where detection and treatment can be most effective. For the clinician, when microscopic tissue changes correlate with macroscopic disease, the diagnosis is more precise and timely, and the treatment is better informed. Motivated by this need, the last decade and a half have experienced extraordinary advances in high-resolution cameras that peer into the eye and capture images of the retina many times sharper than the best clinical instruments, so sharp that individual cells can be observed. Unfortunately, imaging at the cellular level has yet to translate from the laboratory to the clinic where its most significant impact awaits. A major technical obstacle is a lack of computing power. Cellular-resolution cameras that provide volume images of the retina produce streams of enormous data sets (100’s of Gigabytes in size and acquired at high speeds, typically 0.5 Gigabyte/s) that require intensive computations to generate and display images. In contrast, modern retinal management requires rapid turnaround from the diagnostic test to the clinician. This IUCRG aims to accelerate the computations by several orders of magnitude by taking advantage of the latest developments in parallel processing at IUPUI and that in cellular-resolution ophthalmoscopy at IUB. Thus this collaborative effort brings together strikingly different, but critical expertise from different IU campuses to transform a powerful imaging technology from one solely for laboratory research to one that also encompasses clinical studies.

Identifying post-translational modifications in protein complex assembly through STAP; Amber Mosley (School of Medicine), Andrew Kusmierczyk (School of Science, IUPUI)

Proteins carry out most of the work inside a cell, frequently as part of large multi-protein complexes. The better part of the last half-century has been spent trying to determine what these complexes look like and how they function. Yet how these complexes are put together, or assembled, in the first place is an important piece of the puzzle that is not well understood. We know that the function of these multi-protein complexes is regulated by a host of reversible chemical alterations called post-translational modifications (PTMs). There is very good reason to suspect that these PTMs will also regulate how multi-protein complexes are assembled. But these assembly-specific PTMs are needles in a cellular haystack because they are only a tiny fraction of all the PTMs present on all the multi-protein complexes in a cell at any one time. The goal of this research is to develop a method to identify assembly-specific PTMs. Our method combines the genetic, biochemical, and proteomics expertise of both labs. The genetic component relies on a unique assay that will allow us to find the PTM “needles” by essentially removing the haystack, that is to say by getting rid of the noise coming from all the other PTMs. Biochemical purification and state-of-the-art proteomics approaches will then be used to identify these assembly-specific PTMs. We will initially target a single multi-protein complex for our analysis, the proteasome, a machine used to dispose of cellular proteins, but we envision our method being applicable to other complexes as well.

Posttranslational analysis in a novel genetic model of Parkinson's disease; Richard Nass (School of Medicine), Jonathan Trinidad (College of Arts and Sciences, IU Bloomington)

Parkinson’s disease (PD) results in the loss of dopamine producing cells in the brain. The disorder is characterized by tremors, stiffness in the limbs and trunk, slowness of movement, and sometimes depression and other emotional changes. The vast majority of PD cases likely involve a combination of both genetic and environmental contributions. There is currently no cure for the disease. Our studies model PD in a small nematode called C. elegans. The nematode’s nervous system on the molecular level is highly similar to our nervous system, and genes involved in developing PD, or environmental chemicals believed to contribute to the disorder also cause the dopamine neuron to die in the worm. The animals are also largely transparent which allows us to easily examine the dopamine neurons. We have recently identified a gene in the nematode that makes these neurons particularly sensitive to PD-associated genetic mutations and neurotoxicants. This gene is also found in humans, and may play a role directly or indirectly in modifying proteins through a process called post-translational modifications. We are developing novel protocols and techniques utilizing a mass spectrophotometer to identify modified proteins that may be involved PD-associated cell death. These studies may identify proteins and molecular pathways involved in the neurodegeneration, and help elucidate novel therapeutic targets to combat this devastating disorder.

Relating electrophysiology and symptoms of Parkinson’s disease; Leonid L. Rubchinsky (School of Science, IUPUI), S. Elizabeth Zauber (School of Medicine)

About one million Americans suffer from Parkinson’s disease (PD). While it is well known that PD results from the degeneration of dopaminergic neurons, little is understood about how this loss results in symptoms of the disease, both motor and non-motor. Recent studies suggest that low levels of dopamine lead to pathological patterns of communications between neurons in the brain: some neurons are more in synch with each other, than they should be. Thus instead of overall high or low activity of brain areas subtle features (when exactly neurons are active with respect to each other) appear to be relevant for the PD symptoms. This study will use our recently developed data analysis methods to detect and describe the fragile and intermittent neuronal synchronization. Our expertise in neural data analysis and computational neuroscience and in surgical treatment of PD will help to create the link between physiological data (neural activity) with clinical information about motor and non-motor PD symptoms. We will determine how the relevant (but hard-to-detect) features of the neuronal physiology relate to the clinical behavioral features of PD. The understanding of how the symptoms are correlated with neural activity is significant in two aspects. First, this will contribute to the general understanding of how brain circuits in the dopamine-deprived brain generate the motor symptoms. Second, it may improve ways of antiparkinsonian electrical brain stimulation. For example, it may be possible to target the particular features of neural activity to suppress a particular constellation of symptoms without substantial side effects of stimulation.

Social SLAM: Creating Dynamical Socio-Environmental Models for Mobile Robots; Selma Šabanović, Luis Rocha, Matthew Francisco, Alin Cosmanescu (School of Informatics and Computing)

The Social SLAM project seeks to enable robots to navigate and interact with the social space of the home by understanding where people are within it, when people arrive in a space, how long they will stay, and where the robot should position itself in the social space at any given time. This capability will be necessary as robotic technologies become increasingly present in diverse households. To extend the widely used robot navigation method of simultaneous localization and mapping (SLAM) to social space, we are developing a suite of computational tools that combine low resolutions sensors (e.g. vibration, light, IR), off-the-shelf 2-dimensional SLAM, artificial-life, agent-based modeling of social systems, and machine learning techniques. These tools will produce an ensemble of predictions of the current social and physical state of the environment, which the robot will then be able to use as an input to a “social-reasoning engine” which will induce a robotic action. We expect our tools to benefit robotics by providing an empirically grounded way to create robots that are more aware and responsive to social situations. It should also contribute to the sciences of human movement and social dynamics, research on the ecology of human households, and the design of new services and technological solutions for the home. Our interdisciplinary team combines expertise in human-robot interaction and the social study of technology, artificial intelligence, bio-inspired computing, embodied intelligence, complex systems, computer modeling of social systems, and electronic system design.

A Novel Retinal Imaging Approach to Diagnose Glaucoma; Brian Samuels and Lyne Racette (School of Medicine), Gavriil Tsechpenakis (School of Science, IUPUI)

Glaucoma is one of the leading causes of significant vision loss and legal blindness in the United States and worldwide. This disease is characterized by progressive damage to the retina and optic nerve at the back of the eye. Once vision is lost because of this damage, it is often permanent. Thus, it is imperative that clinicians have the diagnostic tools available to identify glaucoma or its progression at the earliest possible stages in their patients. Our current methods of detecting glaucoma have significant limitations that decrease the sensitivity and specificity of their diagnostic utility. However, recent advances have resulted in the development of spectral-domain ocular coherence tomography (SD-OCT), an ophthalmic imaging technology that allows for retinal and optic nerve head imaging with a resolution of approximately 4 micrometers. We have assembled a dynamic team that has expertise in the diagnosis and treatment of patients with glaucoma, clinical research identifying visual dysfunction in glaucoma patients, and medical image computing so that we can develop a novel ophthalmic image analysis program using this powerful SD-OCT technology. We plan to determine retinal thickness in bins that follow the anatomic arcuate retinal nerve fiber layer distribution as it courses through the macula. We believe that using SD-OCT imaging technology in this manner will allow us to create a diagnostic test that is both highly sensitive and specific for the retinal and optic nerve damage caused by glaucoma.

Discovering New Particles with Big Data Analytics on the Cloud; Adam Szczepaniak (College of Arts and Sciences, IU Bloomington), Geoffrey Fox (School of Informatics and Computing)

Spectacular new discoveries and advances have recently been made in understanding the origin of the visible matter that is dominated by nucleons the building blocks of atomic nuclei. However, the origin of Confinement, which is the distinguishing feature of the underlying theory of strong interactions, remains mysterious. It seems to prohibit the isolated elementary quarks and gluons, the electuary constituents of the nucleon to exist freely in nature. Understanding the origin of confinement is one of the fundamental questions in physics. Protons, neutrons and other hadrons are the bound states of quarks and gluons allowed by confinement. Studies of individual hadrons and their interaction offer a unique window into this fundamental phenomenon. The unique features of the underlying theory of strong interactions also make it an attractive template for constructing theories beyond the Standard Model of fundamental interactions. Developments in particle accelerators and detection techniques have led to a new generation of experiments in hadron physics that are flourishing around the world. The new experiments at these facilities generate complicated data sets, which demand a qualitatively new level of sophistication in analysis never achieved before.The objective of the project is to develop new theoretical tools and underlying computational services for analysis of large statistics data sets from current and future experiments in hadron spectroscopy with the goal to search for new hadrons, the so called, hybrids and glueballs, which a expected to carry some unique signatures of the confinement phenomenon.

Localizing the skeletal effects of the serotonin transporter; Stuart Warden (School of Health and Rehabilitation Sciences), Teresita Bellido (School of Medicine)

Bone loss and the associated increase in skeletal fragility with aging is an ongoing problem. The underlying cause of bone fractures in the elderly is multifactorial, but is influenced in part by how much bone is gained during growth and how much is lost during aging. We recently observed the serotonin transporter influences bone health. In particular, blocking the transporter causes a reduction in the amount of bone being formed and an increase in the amount being removed. These observations are clinically important as the serotonin transporter is the target of widely-prescribed selective serotonin reuptake inhibitors (SSRIs) which block the transporter and are used to manage depressive and anxiety disorders. Clinical use of SSRIs has been associated with reduced bone health and an increase in fracture risk. It is not currently known whether the bone effects of the serotonin transporter are due to blockade of the transporter in bone itself or due to upstream effects in sites such as the gut or brain. Studies in this project will establish a novel mouse model wherein the serotonin transporter can be blocked in isolated cells and tissues, and perform preliminary studies to determine if blocking of the transporter solely in bone cells contributes to the negative bone effects observed with SSRIs.